Biosimilars China Guideline

Dr Dr Michel Mikhail

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Contents

Regulatory context of biologicals in China

Decree 28 issued by SFDA October 2007

Proposed biosimilars guideline 10/29/14

Reference drugs to use

Non-Clinical Comparability Studies: in-vitro

Non-Clinical pK/PD Studies: in-vivo

Immunogenicity and toxicity testing: animals

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Contents (Contd.)

Extrapolation and Pharmacovigilance

pK/PD clinical studies: in-vivo patients, equivalence design

Immunogenicity testing: patients

Regulatory Context of Biologics

in ChinaRegulatory environment: there are two

mandatory requirements to register an imported

drug product or biological in Asia

Local clinical data needed eg including China in

Multicenter Trials

Minimal number of Chinese patients in trials is defined in the

regulation

Need foreign Certificate of an approved

Pharmaceutical Product (CPP) at the time of NDA

submission (same as for LATAM) 4

Regulatory Context of Biologics

in China (2)There are different pathways and/or data requirements

for imported drugs vs. locally manufactured drugs,

chemical vs. therapeutic biologics

Imported product: Clinical trial application (CTA) can

be filed once the drug enters phase II outside China

Local product: CPP is not needed, but the regulatory

pathway is designed for a China-only development.

CTA can only be filed once manufacturing transfer is

done.

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Regulatory Context of Biologics

in China (3)Main challenges

Timelines are long: CTA review 19 - 22 months

Limited guidance during development due to

SFDA lack of resources & expertise

Extensive quality dataset is requested early in

development

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Decree 28 issued by SFDA

in October 2007Technical and dossier requirements

Annex 3, SFDA Decree 28, for the regulatory requirement of

biologics

Centre of Drug Evaluation (CDE) issued 27 technical

guidances for biologics

IND dossier is NDA-like

CMC is required

API and finished dose manufacturing process, process control

and process validation report

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Decree 28 issued by SFDA

in October 2007 Describe cell bank, analytical procedures

Conduct QC verification for biological products, as part of

the CMC review

Types of Biologicals which Require

Phase I/II/III TrialsBiological products not yet marketed overseas

or in China

mAbs

Gene therapy, somatic cell therapy

Allergen products.

Multi component products having extracted or

fermented bioactivity from human and/or

animal tissues and/or body fluid9

Types of Biologicals which Require

Phase I/II/III Trials (2)New combination product made from the

already marketed biological products.

Imported product approved overseas

Strains used for unapproved micro-ecological

products

Types of Biologicals which Require

Phase I/II/III Trials (3)Products without the same structure of an already marketed product, not yet

marketed in China or overseas (including amino acid locus mutation, which

absence or modification is caused by a different expression system, deletion,

changes or chemical modifications of the product).

Products manufactured differently from the already marketed product such

as use of different expression system or host cell.

Products made for the first time with r-DNA technology such as use of r-

DNA technology to replace chemical synthesis, tissue extraction or

fermentation technology

Products changed from non-injection to injection, or topical to systemic use,

and not yet marketed domestically or overseas.

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Types of Biologicals which Require

Only Phase III TrialsThe marketed products with a change in dosage

form but no change in route of administration.

Products with a change in route of

administration (excluding the previous list).

Biological products (Biosimilars) of SFDA-

approved biological products

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Biosimilars

29 October 2014Guidelines for R&D and Evaluation Techniques

of Biosimilars

Draft Guideline published by Center for Drug

Evaluation (CDE), SFDA on October 29, 2014

Final Guideline published by Center for Drug

Evaluation (CDE), SFDA in May 2015 in

Chinese language only.

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Biosimilars

Introduction:

China was actively involved as WHO Member

in the Development of the WHO Biosimilars

Guidelines

It was expected that China simply adopts the

WHO Biosimilars Guideline rather than

developing their own Guideline

However China Published the draft of their own

Biosimilars Guideline on 29 October 2014 14

Reference drugs to use

Originator products registered in China with the

State Drug Administration with established safety and

efficacy = Reference Listed Biologics (RLBs)

As initially mentioned in the Draft Guideline, the

RLBs used in different stages of R&D to the greatest

possible extent shall be products from the same batch

(!) This was removed in the Final Guideline.

RLBs not commercially available in China may be

acquired through appropriate ways and comply to other

national regulations15

Commentary: Chinas RLB

Less strict than Canada; but using RLB from

same batch for all R&D is unreasonable and

wont capture drift. Also is this logistically

feasible?

After having received many comments on this

issue, the SFDA has deleted this requirement

from the Final Guideline published in May 2015.

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Non-Clinical Comparability

(NCC) Studies: in-vitroIn NCC in-vitro studies, if little or no

differences are found, some subsequent

comparability tests may be exempted

At least three batches shall be used to

determine in-vitro comparability

The manufacturing process of the biosimilar

shall be designed to the RLBs critical quality

attributes and be identical in the sequence of

process steps17

Non-Clinical Comparability

Studies: in-vitro (2)Physicochemical properties

Primary and higher order structure differences

Translational modification differences to N-terminal

and C-terminal Amino Acid sequence

Glycosylation modification to structure and glycoform

of the sugar chains

Biological activity

Determine significant function differences between

the biosimilar and the RLB18

Non-Clinical Comparability

Studies: in-vitro (3)Purity and Impurity

Hydrophobicity, electric charge, molecular size

variants, translational modification (including

glycosylation)

Impurity level differences: processes and host cells

Immunological properties of mAbs

Comparability of Fab and Fc including Q1/Q2 of the

affinity, CDC/ADCC activity with antigens and

receptors such as FcRn, Fc and ClQ. 19

The variable region (Fab)

Function: to accommodate the diverse antigen-binding

specificities

The antigen-binding site is formed by the inter-twining

of the light chain variable domain (VL) and the heavy

chain variable domain (VH).

Each V domain contains 3 short stretches of peptide

Complementarity Determining Regions (CDRs)

the prominent determinants of antigen-binding affinity

and specificity20

The constant region (Fc)

The heavy chain contains 3 constant domains: CH1,

CH2, and CH3.

CH2 and CH3 domains : interactions of the IgG

molecule with various components of the immune

system

binding C1q activates the complement cascade & elicits

Complement-Dependent Cytotoxicity (CDC)

binding to Fc receptors elicits Antibody-Dependent

Cellular Cytotoxicity (ADCC).

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Structure and functions of

monoclonal antibodies

Fc

FcgR receptor

FabLight chain

Heavy chain

VH

VLCDR

C1Q binding site

FcgR binding site

Antigen-Binding domain

Effectordomain

FcRn binding site

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Structure and functions of

monoclonal antibodiesThe Fab and Fc portions have 2 different

functions.

- Fab (particularly in the variable and

hypervariable regions) is responsible for Antigen

Binding, therefore called Antigen-Binding

Domain.

- The Fc portion also known as the Effector

domain, is responsible for the complement

fixation and interaction with the Fc receptors.23

Non-Clinical Comparability

Studies: in-vitro (3)Purity and Impurity

Hydrophobicity, electric charge, molecular size

variants, translational modification (including

glycosylation)

Impurity level differences: processes and host cells

Immunological properties of mAbs

Comparability of Fab and Fc including Q1/Q2 of the

affinity, CDC/ADCC activity with antigens and

receptors such as FcRn, Fc and ClQ. 24

Commentary: Chinas NCC in-

vitroVery abbreviated, lacks focus on biosimilarity,

but aligned with WHO guideline

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Non-Clinical pK/PD Studies: in-

vivo on animalspK studies on relevant animal species in multiple dose groups

on the basis of a single dose or a r