Overview of biological product evaluation in CDE, CFDA · PDF fileOverview of biological product evaluation in CDE, CFDA ... The total number of yearly accepted biological product

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Overview of biological product evaluation in CDE, CFDA

CDE CFDA

Jianhui LUO

Office of Pharmaceutical Science of Biological Products

[email protected]

WCBP, Washington, DC.

Date: Jan. 24, 2017

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Outline

• Introduction of CDE and biological product review

• Changing undergoing in CDE

• Guidelines and hot topics concerning biologics

• New concept, practice & challenge

• Review of import biological product applications by CDE from 2014 to 2016

CDE CFDA

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Part 1:Introduction of CDE and biological product review

CDE CFDA

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Organization Frame Diagram of CDE

Office of

Pharmaceutical

Science of

Biological

Products

Office of

Pharmaceutical

Science of

New Drug

Office of

Pharmaceutical

Science of

Generic Drug

Office of

clinical

Evaluation

of TCMs

and Ethno-

Medicine

Office of

Pharmaceutical

Science of

TCMs and

Ethno-

Medicine

Office of

Biostatistics

and Clinical

Pharmacology

Office of

Clinical

Evaluation

of Biological

Products

Office of

Pharmacology

and

Toxicology

Office of

Clinical

Evaluation

Ⅰ

Office of

Clinical

Evaluation

II

Director

Administrative

Office

Office of

Management and

Communication

Office of Quality

Management

Office of Human

Resource

Office of Finance

Chief Scientist

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Functions of CDE

05

06

Technical review of drug

registration applications

(IND/NDA/supplemental )

Other tasks assigned

by CFDA

Guiding drug review

activities of local

authority

Involved in developing

regulations, rules and

policy

Following up application

trend and legal issues

related to drug

evaluation

International collaboration

and cooperation

Duties

and

Responsibilities

01

03

04

6

Divisions involved in biologics evaluation

• CMC division

• Pharmacology and toxicology division

• Clinical division

• Biostatistics division

CDE CFDA

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Review Process

Data Receiving

Task Assignment

Professional Team

Review

Comprehensive Evaluation

Technical Review

Local

Authority

Complaint and

Service Center

Provincial

Institute for

drug control

National

Institutes for

Food and

Drug Control

Center for Food and

Drug Inspection of

CFDA

Advisory Panel

Center for Drug

Reevaluation of

CFDAChinese

Pharmacopoeia

Commission

SponsorsDomestic

Application

Certificate of

Analysis

Approved new

drug generic

name

Validation of OTC

drug instructions

On-site

inspection

before approval

On-site

inspection

Domestic application

data

On-site inspection report

CFDA

CoA of generic

drugCoA of new drug

Import

Application

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Part 2:Changing undergoing in CDE

CDE CFDA

9CDE CFDA

The Opinions of the State Council

on Reforming the Evaluation and Approval System of Drugs and Medical Devices

(No. 44[2015] of the State Council),

——issued by the State Council On Aug. 18, 2015,

—— the milestone of China’s reform on Drug Evaluation and

Approval system.

10CDE CFDA

To resolve the backlog of drug review and approval, to exercise strict control over the

approval of oversupplied drugs.

To optimize the review and approval procedures of innovative drugs.

To adjust drug registration classification, defining the new drugs more stringently.

To strengthen the clinical test verification.

To carry out the pilot work of Drug Marketing Authorization Holder (MAH) System

Others: Service based on the mode of government purchase;

Quality consistency evaluation for generic drugs;

Simplified drug approval process ;

Strengthened communication and information disclosure in review and approval.

What’s said in the State Council ’s document?

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Changing undergoing in CDE, CFDA

Applicable guidelines issued by CFDA or other international

agency

Guidelines on phase I clinical trial (for comments and

suggestion), with simplified data requirements for application

dossier

Application and designation for priority review, pre-IND meeting,

and accelerated approval

CMC Changes during development and / or post marketing，

developing guidelines

CDE CFDA

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Part 3:Guidelines and hot topics concerning biologics

CDE CFDA

• Biosimilars

• Recombinant Mab application and approval

• Innovative biologics

• Cellular therapy

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I. Biosimilars

Similar not identical, biomedicinal similar

Comparability study

Original as comparator

Critical process control, Critical quality attributes similar

Well designed and controlled Clinical trial, PD marker may be

used as clinical surrogate endpoint

Post market surveillance, immunogenicity

CDE CFDA

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Diagram for Decision-making of Biosimilar Development

Similar Difference

Difference

PD,PK,

immunogenicityPD,PK,

toxicity

PD，PK，immunogenicity

Clinical-

pharmacology，safety and

efficacy

Not similar

Not similar

Not similar

uncertainty

Biosimilar

CMC and

quality

comparing

study

Non-clinical

Clinical

uncertainty

Similar

Similar

Carefully

going onBetter to quit

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II. Recombinant Mab application and approval

Antigen target or clinical indication

Clinical trial approved

Marketing application approved

Application under review

CDE CFDA

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List of Mab ( hot target and indication)

Antigen target

EGFR, IgE, TNF-α,IL-12,IL-6R,IL-8 DR5, RANKL, BLyS, CD20,VEGF, CD38,

HER2, CD52, CTLA-4, LFA-3, CD-22, CD-11a, CD25, PD-1, PD-1L, IL-17A, IGF-

1R and so on

Disease or indication

Tumor, autoimmune disease, infectious disease, respiratory

disease, cardiovascular disease, neuron disease, and so on

CDE CFDA

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III. Innovative biologics

Unmet medical needs

Accelerated approval procedure, top priority review

Pre-IND meeting and pivotal clinical trial meeting

Guidance on phase I clinical trial application （for

comments and suggestion）

Conditional approval on market

Committed study

CDE CFDA

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IV. Cellular therapy

Guideline on Pre-clinical Trial and Quality Control of

Stem Cell Products Intended as Medicinal

Technology, issued jointly by CFDA and NHFPC in 2013.

Measures for the Administration of Clinical Trials for Stem Cell

Products, issued by NHFPC in 2015 .

- Specifying the institute’s qualification, the clinical trial procedure,

reporting system, experts committee, supervision, etc.

Drafting guidelines on cellular products intended for biologics

registration, by CDE in 2016 (for public consideration).

Note: NHFPC, National Health and Family Planning Commission of the PRC

CDE CFDA

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Part 4:New concept, practice & challenge

CDE CFDA

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New concept & challenge (Definition and understanding of “biosimilar”)

Physical-chemical structure vs. biological function,

apparently characteristic vs. substantial effect ;

Pharmaceutical attributes (product quality)

vs. clinical therapeutic performance (clinical value);

Local aspects of data vs. whole profile of product;

Clinical evidence, totality.

CDE CFDA

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New practice and challenge(Continuous manufacturing and QbD)

Batch or lot definition, quality consistency;

Variation control; space design, validation;

Manufacturing cycle, “holding”, in process control, PAT;

Homogeneous, pooling & combining;

Manufacturing capacity and matching between steps,

seamless connection between upstream and downstream,

and among process facilities or steps;

Model separation and combination in system.

CDE CFDA

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Part 5:Review of import biological product applications (2014～2016)

CDE CFDA

• Application acceptances and review completions

• Comparison between import applications and

domestic applications

• Priority review list

23CDE CFDA

Acceptances and completions of biological product review from 2014 to 2016 (annual task )

Note: Review completions means the review tasks which have completed by the CDE and submitted to the CFDA.

The total number of yearly accepted biological product applications is in the range of 400 to 600 over

the past three years (by acceptance numbers). Due to the effort of resolving the backlog of drug review

and approval, 2016 has seen a significantly progress in the number of applications completed. In 2016,

the number of tasks completed is 1.5 times that of accepted tasks.

454

558

408498 524

638

0

100

200

300

400

500

600

700

2014 2015 2016

Acceptance

Completion

24CDE CFDA

Of the accepted tasks, vaccine tasks are less than therapeutic tasks.

It is the same with the tasks completed .

Note: Review completions means the review tasks which have completed by the CDE and submitted to the CFDA.

Acceptances and completions of biological product review from2014 to 2016 (vaccine vs. therapeutic product )

0

50

100

150

200

250

300

350

400

450

2014 2015 2016

Acceptance

Vaccine tasks

Therapeutic tasks

0

100

200

300

400

500

600

2014 2015 2016

Completion

Vaccine tasks

Therapeutic tasks

25CDE CFDA

The number of import applications is comparable with domestic applications over 2014～2016.

The proportion of completed tasks to accepted tasks for import applications is comparable with that for

domestic applications.

Annual

number

Total

number

Comparison between import applications and domestic applications from 2014 to 2016 (number)

0

50

100

150

200

250

300

350

400

2014 2015 2016

Domestic applications

Acceptance

Completion

0

50

100

150

200

250

300

2014 2015 2016

Import applications

Acceptance

Completion

51.09%48.91%

Acceptance

Domesticapplications

Importapplications

52.14%47.86%

Completion


Importapplications

26CDE CFDA

For vaccine review, domestic applications are more than import applications.

Contrarily, the domestic applications are less than import applications for therapeutic product review.

Vaccine

Therapeutic product

Comparison between import applications and domestic applications (vaccine vs. therapeutic product)

0

20

40

60

80

100

120

2014 2015 2016

Acceptance


Importapplications

0

20

40

60

80

100

120

2014 2015 2016

Completion


Importapplications

0

50

100

150

200

250

2014 2015 2016

Acceptance


Importapplications

0

50

100

150

200

250

300

2014 2015 2016

Completion


Importapplications

27CDE CFDA

Among the import applications of biological products, the supplementary applications are the most,

accounting for more than 50%, followed by the IND applications.

The numbers of IND applications and BLA increased stably these years.

Annual

number

Total

number

Acceptances and completions of import products from 2014 to 2016 (IND/BLA/Supplemental/re-registration)

0

50

100

150

200

2014 2015 2016

Acceptance

IND

BLA

Supplementaryapplication

Importre-registration

0

50

100

150

200

2014 2015 2016

Completion

IND

BLA



34.47%

3.14%57.74%

4.65%Completion

IND

BLA



29.84%

4.59%61.98%

3.59%

Acceptance

IND

BLA

Supplementary application


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Among 15 (by acceptance numbers) or 7 (by products) priority review tasks in 2016, only 2

are domestic applications.

Biological products listed in priority review in 2016Acceptance

number

Type Name Indications Stage

1 JXSS14xxxx BLA Adalimumab Solution for Injection Rheumatoid arthritis

(RA)

Import

application

Being reviewed

2 JYSB14xxxx Supplementary

application

Insulin Glargine Injection

Note: the same product

Diabetes type 1 and

type 2

Import

application

Approved

3 JYSB14xxxx

4 JXSS16xxxx BLA Reassortant Rotavirus Vaccine,

Live,Oral,Pentavalent(Vero Cell)

Prophylactic vaccine Import

application

Being reviewed

5 JXSS16xxxx BLA Tocilizumab Injection

Note: the same product with different

specifications

Active systemic

juvenile idiopathic

arthritis(sJIA)

Import

application

Approved

6 JXSS16xxxx

7 JXSS16xxxx

8 CXSL16xxxx IND Recombinant Human Coagulation Factor Ⅷfor Injection

Hemophilia A Domestic

application

Waiting for sponsor's

reply

9 CXSL16xxxx IND Therapeutic Hepatitis B Adenovirus

Injection

Chronic hepatitis B Domestic

application


reply

10 JXSL16xxxx IND Recombinant Coagulation Factor VIII for

Injection

Note: the same product with different

specifications or different target

populations

Hemophilia A Import

application


reply11 JXSL16xxxx

12 JXSL16xxxx

13 JXSL16xxxx

14 JXSL16xxxx

15 JXSL16xxxx

CDE CFDA

29CDE CFDA

Thank you

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Back up slides

CDE CFDA

31CDE CFDA

Acceptances and completions of biological product review from 2014 to 2016 (IND/BLA/Supplemental/re-registration)

The supplementary applications are the most, accounting for nearly 50% of all the applications, followed

by the IND applications, then the BLA and the import re-registration applications.

Annual

number

Total

number

0

50

100

150

200

250

300

2014 2015 2016

Acceptance

IND BLA Supplementary application Importre-registration

0

50

100

150

200

250

300

350

2014 2015 2016

Completion

IND BLA Supplementary application Importre-registration

42.11%

6.27%

49.86%

1.76%

Acceptance

IND

BLA



42.65%

6.99%

48.13%

2.23%

Completion

IND

BLA



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Overview of biological product evaluation in CDE, CFDA · PDF fileOverview of biological product evaluation in CDE, CFDA ... The total number of yearly accepted biological product