Transcript Regulatory Issues regarding recovery and purification: How

BioSimilars in EU and US
Scientific, Legal and Regulatory Issues
Michael Marshall Ph D
Regulatory Affairs
Novo Nordisk A/S
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Whats in the name?
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Innovator
Product
Generic
Product
Quality
Nonclinical
Clinical
Bioequivalence
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Directive 2004/27/EC amending 2001/83/EC
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
Note: Directive 2003/63/EC refers to generics as “essentially similar”
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Innovator
Product
BioSimilar
Product
Quality
Nonclinical
Clinical
Bioequivalence
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Structure of Biologicals is complex
Factor VII
Insulin
O
OH
O
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O
Aspirin
No clinical effect
Clinical effect
Antibodies to drug
Impurities
Impurities
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Active
Substance
Purification
Recovery
Fermentation
Cell Bank
Host Cell
Formulation
Directive 2004/27/EC amending 2001/83/EC
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 (preclinical) or efficacy (clinical), or both.
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‘
Directive 2004/27/EC amending
2001/83/EC
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.’
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Directive 2003/63/EC amending 2001/83/EC
Annex 1 relating to documentation requirements
Part 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
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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
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The Guidelines
Comparability
General (ICH)
General (3207)
Non-clinical/clinical (3097)
BioSimilars
General (437)
Non-clinical/clinical (42832) Quality (49348)
Annexes
Insulin (32775) h-GH (94528) G-CSF (31329) EPO (94526)
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Guideline on Similar Biological Medicinal
Products (CHMP/437/04)
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.
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Comparability Data
Clinical
Quality
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Non
Clinical
Scope of Non-clinical and Clinical Studies
Regulator
Innovator
Safety and Efficacy
must be ensured
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BioSimilar
Manufacturer
Reduced testing
justified
The Quality Guideline
Reference
Medicinal
Product
Comparability
•Characterisation of DS
Structure
PTM
•Physicochemical
•Impurities
- Product related
•Accelerated stability
Validate
Active
Substance
Process related
Impurities
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BioSimilar
Medicinal
Product
Validate
Active
Substance
Comparative Non-Clinical and Clinical studies
Product
Insulin
h-GH
Non-clinical
In vitro PD
Tox: 4 weeks
repeat dose
In vitro/vivo PD
Tox: 4 weeks
repeat dose
Clinical
PK/ Efficacy
PD

No
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Safety
Immunogenicity:12 months
(6 months comparative)
Local reactions
Data from Efficacy trial
and 12 months Immunogenicity
GCSF
In vitro/vivo PD
Tox: 4 weeks
repeat dose
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6 months study including
Immunogenicity
EPO
In vitro/
In vivo PD
Tox: 4 weeks
repeat dose


Data from Efficacy trial and12
months Immunogenicity
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Status in U.S.
• 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
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Regulatory legislation in US
Food, Drug and Cosmetic Act
Insulin, h-GH
Hatch Waxman Act 1985:
Abridged regulatory route
for Generics
1. FD&C Act Section 505 (b)(2)
2. FD&C Act Section 505 (j)
Not decided if FOBs can use
these routes
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Public Health Service Act
Most Biologicals
No Regulatory route for FOBs
FD&C Act Section 505 (b)(2)
• 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)
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FD&C Act Section 505(j)
• “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
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Conclusions
• BioSimilars are not generics
 Scientific barriers to demonstration of Comparability
• EU
 The legislation and regulatory guidelines are in place
 One BioSimilar has already been approved and more
approvals are in the pipeline
• US
 Scientific, legal and political issues not yet resolved
 Slower than EU but FOBs will eventually come
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