follow-on biologics guidelines in japan - overvie kobayashi... · although usually different...

a Novartis company

Follow-on Biologics Guidelines in Japan

- Overview -

Junichi Kobayashi

Development

Sandoz K.K., Japan

The 12th Annual IGPA Conference

Montreal, CanadaSeptember 30th – October 2nd, 2009.

2 J.Kobayashi/Oct.01.2009./

Topics

Regulations for Follow-on Biologics

Summary of the Follow-on Biologics

Guidelines in Japan


Guidelines in Japan


Applied to products submitted as FOB

on April 1st 2009 and after

In case a product already submitted before

April 1st 2009 and assessed as FOB,

the GLs are individually applied

Applied to products submitted as FOB

on April 1st 2009 and after


FOB Guidelines issued on March 4th 2009

ELD Notification No. 0304007

The draft GLs released on September 17th 2008

for collecting public comments

ELD: Evaluation and Licensing Division


“Handling of Non-proprietary Names and Brand Names

pertaining to Follow-on Biologics”

newly issued ELD Notification No. 0304011

“Points to consider when filing Approval Application for

Follow-on Biologics”

revision of the existing notification PFSB/ELD Notification No. 0331009

“Approval Application for Follow-on Biologics” added

revision of the existing notification PFSB Notification No. 0304004

Guidelines related Notifications

Issued on the same day

PFSB: Pharmaceuticals and Food Safety Bureau

ELD: Evaluation and Licensing Division

“Approval Application for Follow-on Biologics” added

revision of the existing notification PFSB Notification No. 0304004

“Points to consider when filing Approval Application for

Follow-on Biologics”

revision of the existing notification ELD Notification No. 0331009


Abbreviated data confirmed

Definition of FOB confirmed

PFSB Notification No. 0304004

An FOB is a drug comparable to a biotechnological

product, which has already been given MMA

(Manufacturing and Marketing Authorization)

Regulatory pathway for FOB newly established PFSB Notification No. 0304004

Regulatory pathway for FOB newly established PFSB Notification No. 0304004

What was changed?

Abbreviated data confirmed

Definition of FOB confirmed

PFSB Notification No. 0304004

An FOB is a drug comparable to a biotechnological

product, which has already been given MMA

(Manufacturing and Marketing Authorization)

Submission fees or other costs not abbreviated

Same as those of new drug application

unfortunately unchanged ca. 330,000 $/ 1st strength + ca. 45,000 $/ add. strength X n

(ca. 230,000 Euro) (ca. 32,000 Euro)


Mandatory origin, background of the discovery, use In foreign countries, etc.

manufacturing methods, specification, and test methods, etc.

long-term storage stability

pharmacology data to support efficacy

repeated dose toxicity

clinical trials

Case-by-case basis

stress and/or accelerated stability

absorption, distribution, metabolism, excretion, other PK data

single dose toxicity, local irritation, and other toxicity

Not required

secondary and safety pharmacology, other pharmacology

bio-equivalence

genotoxicity, reproductive toxicity, carcinogenicity,

other ordinal safety studies

Data required for Submission


Topics



Guidelines in Japan


Comparison of GLs b/w EU and JP

EU GLs

User Guide

Overarching Guideline

(CHMP/437/04)

General Description

Quality Issues

Non-clinical issues

Clinical issues

Class Specific

Insulin

G-CSF

Somatropin

Epoetin

Others

JP GLs

User Guide

Not issued

General Description Introduction Scope of Application General principle Manufacturing & Quality Issues Specification & Test Methods Non-clinical issues Clinical issues Post-marketing surveillance

Class Specific

Not available


General Description

Introduction

Scope of Application

General principle

Manufacturing & Quality Issues

Specification & Test Methods

Non-clinical issues

Clinical issues

Post-marketing surveillance


The safety and efficacy not affected by

any variation in quality attribute

Introduction

Highly similar to the reference product

in the quality attribute

Definition of “Comparability”

Highly similar to the reference product

in the quality attribute


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Polypeptides and those derivatives, which are;

produced using microorganisms or cultured cells

highly purified

possible to characterize by a series of appropriate

analytical procedures

Recombinant proteins, which are;

simple proteins

glycoproteins


Subjects of the GLs

Recombinant proteins, which are;

simple proteins

glycoproteins


Basic principle also to be applicable to

non-recombinant proteins or polypeptides

by cell culture or isolation from tissues, etc.


Further application:

Consultation with the Health Authorities

at case by case basis



Excluded products

antibiotics

synthetic peptidesor polypeptides

polysaccharides vitamins

cell metabolites

nucleic acid-based products,allergenic extracts

conventional vaccinese.g. inactivated

pathogenicmicroorganisms

cells, whole blood, orblood cell components


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Manufacturing processes to be originally established

General Principle

Key factors for developing FOBs are;


Quality characterization to be clarified in details


General Principle

Quality characterization

The following 5 items should be investigated

the-state-of-art

technologies

impurities

immunological

properties

physicochemical

properties structure and composition

bio-activities


Higher quality similarity to the reference product

to be demonstrated by referring to ICH Q5E concept

General Principle

Key factors for developing FOBs are;


Quality characterization to be clarified in details

Higher quality similarity to the reference product

to be demonstrated by referring to ICH Q5E concept

Comparability to the reference product to be further

demonstrated by non-clinical and clinical studies


General Description

Introduction


General principle



Non-clinical issues

Clinical issues




Manufacturing processes

Establishment of a highly constant and robust method

more appropriate to search for a safer process,

e.g. serum-free culture

Establishment of a highly constant and robust method

more appropriate to search for a safer process,

e.g. serum-free culture

Host-vector system

Use of the same host cell as the reference product is advisable Use of the same host cell as the reference product is advisable

In case a different type is used In case a different type is used

more quality and safety data focusing on differences

in process- and host cell-related impurities are required

more quality and safety data focusing on differences

in process- and host cell-related impurities are required

Glycoprotein: often difficult to demonstrate comparability

due to presence of significant glycan heterogeneity

Optimum strategy needs to be taken to evaluate effects

of glycan differences on safety and efficacy


To be established by each company independently

ICH Q5A, ICH Q5B, and ICH Q5D


ICH Q5A, ICH Q5B, and ICH Q5D


Cell bank system

Culture and purification processes


Maybe more rational

rather than

to evaluate effects of product on safety

based on established processes and characterization

to simply assess similarities and differences in impurities



Drug product designing

The same administration route, in principle

Not necessary to develop same formulations

(prescription) as the reference product



Stability testing

Long-term stability testing required

shelf-life to be determined by long-term stability

same storage conditions or shelf-life as

the reference product not essential

Stressed and accelerated stability testing also needed

at the case by case basis

ICH Q5C


Comparison with the reference product requested

usually drug products to be compared

desirable to use multiple batches

In case of different quality profiles

impact on safety and efficacy to be confirmed by

non-clinical and/or clinical studies

Comparison with the reference product requested

usually drug products to be compared

desirable to use multiple batches


Quality attribute related comparability

definition of “comparability” depending on

product characteristics

purposes of use and methods at medical practice


Structure & physicochemical properties

amino acid sequence as FOB mandatory

Bio-activities, multiple methods whenever possible

results are considered to be reflected by effects of

higher-dimensional structures

direct comparison of higher-dimensional structures

not always applicable, e.g. hard-to-get substances,

difficult to prepare samples for assay

Bio-activities, multiple methods whenever possible

results are considered to be reflected by effects of

higher-dimensional structures

direct comparison of higher-dimensional structures

not always applicable, e.g. hard-to-get substances,

difficult to prepare samples for assay

Immunological properties, in animals

useful information for assessing quality attributes

including impurities

Comparative studies for demonstrating “comparability”


Structure & physicochemical properties

amino acid sequence as FOB mandatory


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Quality control to be established based on

quality characterization

comparability investigation

batch analysis

and

manufacturing process control tests

In case the reference product is listed in the JP

should follow the JP description

necessary to establish additional S&TM

Quality control to be established based on

quality characterization

comparability investigation

batch analysis

and

manufacturing process control tests


Specification & Test Methods (S&TM)


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Not necessary to conduct direct comparison,

although usually different impurity profiles

to be observed

on the other hand

possible to conduct direct comparison focusing on

toxicity of new types of impurities

Antibody

identification, e.g. neutralizing antibody or not

influence on PK profiles

Not necessary to conduct direct comparison,

because different impurity profiles are usually

observed

on the other hand

possible to conduct direct comparison focusing

on toxicity of new types of impurities

Non-clinical Issues

Toxicology studies


Non-clinical Issues

Toxicology studies other than repeated-dose studies

The following studies not necessary,

unless any particular reasons existing:

safety pharmacology

reproductive & developmental toxicity

genotoxicity

carcinogenicity

other ordinal safety studies


Non-clinical Issues

Pharmacological comparability

Direct comparison required

in vitro bio-assay

e.g. cell proliferation, receptor-binding assay

in vivo animal studies

not necessary,

if in vitro bio-assay is closely associated

with clinical efficacy


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Clinical Issues

Clinical comparability by clinical studies

Because it is difficult to verify clinical comparability

based on quality attributes and non-clinical results,

in general

”step-by-step” and “case-by-case” approach needed

consultation with the Health Authorities

recommended

use of final formulations desirable


Clinical Issues

Design of PK, PD, and PK/PD studies

Same as the

reference product,

or within approved

dose range

Same as the

reference product

conduct study

in each route

Direct comparison

by cross-over

healthy subjects

or patients

Design Primary

parameters

DoseAdministration

route

AUC, Cmax,

PD markers, etc.


In case “Efficacy comparability” is not demonstrated by

“Quality” and “PK/PD”

comparative clinical studies to be conducted (Ph III)

In case “Efficacy comparability” is not demonstrated by

“Quality” and “PK/PD”

comparative clinical studies to be conducted (Ph III)

In case multiple indications are approved with the

reference product

if pharmacological mechanisms are different

among those indications

comparative clinical studies required in each

indication

Clinical Issues

Comparison of clinical efficacy


Execution of repeated dose studies to be considered

for bio-drugs administrated long-term

Execution of repeated dose studies to be considered

for bio-drugs administrated long-term

Possible to investigate safety profiles in

“efficacy comparability studies”

Possible to investigate safety profiles in

“efficacy comparability studies”

Necessary to consider to execute clinical safety studies Necessary to consider to execute clinical safety studies

Clinical Issues

Verification of clinical safety

Immunogenicity to be investigated

identification of antibodies

e.g. neutralizing antibody or not

reduction in efficacy or impact on safety


General Description

Introduction


General principle



Non-clinical issues

Clinical issues



Post-marketing Surveillance

Objective: clarification of safety profiles

PMS Planning

Safety risks envisaged

Traceability assured

Consultation

with Health

Authorities

Submission of file

with PMS plans

Approval & PMS

Execution

Results reported

to Health

Authorities


The Real Last Slide

Thank you very much

for your attention!

If you have any questions in details,

please consult with the Health Authorities

Japan first => http://www.pmda.go.jp/

as it may be the best policy now

&

The Last Slide


Back-up


Back-up / Bio-equivalence Data

Data on BE study required for the following

submission:

Additional dosage forms

Drugs such as biologics of which production

method is modified

Generic drugs (low molecule chemicals)

New drugs other than the following category:

1) new ethical combinations

2) new administration routes

3) new indications

4) new dosage forms

5) new dosage,

6) similar ethical combinations

may be required between

formulations with

different dose strengths

follow-on biologics guidelines in japan - overvie kobayashi... · although usually different...

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