Slide no 1 • •

Michael Marshall Ph DRegulatory AffairsNovo Nordisk A/S

BioSimilars in EU and USScientific, Legal and Regulatory Issues

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Whats in the name?

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InnovatorProduct

GenericProduct

Quality

Clinical

Non-clinical

Bioequivalence

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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”

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InnovatorProduct

BioSimilarProduct

Quality

Clinical

Non-clinical

Bioequivalence

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Structure of Biologicals is complex

OH

O

O

O

Aspirin

Insulin Factor VII

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ActiveSubstance

Impurities Formulation

PurificationRecovery

FermentationCell BankHost Cell

Antibodies to drug

Clinical effectNo clinical effect

Impurities

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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

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‘

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

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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

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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

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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)

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Quality

Clinical

Non Clinical

Comparability Data

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Safety and Efficacymust be ensured

Reduced testingjustified

Scope of Non-clinical and Clinical Studies

RegulatorInnovator

BioSimilarManufacturer

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ReferenceMedicinalProduct

BioSimilarMedicinalProduct

•Characterisation of DSStructure PTM

•Physicochemical•Impurities- Product related•Accelerated stability

Process related Impurities

ActiveSubstance

ActiveSubstance

Comparability

Validate Validate

The Quality Guideline

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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

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• 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.

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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

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•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)

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•“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)

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• 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