ZHANG WEI Director General, Department of Drug Registration May 17, 2010, Beijing

Establishment and Implementation of Regulations and Policies on Drug Registration and Impacts on the Pharmaceutical Industry of China

ZHANG WEIDirector General, Department of Drug

RegistrationMay 17, 2010, Beijing

2nd DIA China Annual Meeting

Overview

1. Progress on the Laws and Regulations concerning Drug Registration in 2009

2. Major Measures adopted on Drug Registration in 2009

3. Statistics on China’s Pharmaceutical Industry in 20094. Approval on Drug Registration in 20095. International Exchanges on Drug Registration in 20096. Progress on Anti-Counterfeiting Drugs in 2009

Progress on Laws and Regulations concerning Drug Registration

Laws and Regulations on Drug Registration

Drug Administration

Drug Registration

Technical Guidelines on Drug Research

laws

Administrative regulationsregulations

SFDA decrees


Normative documents

Laws and Regulations onDrug Administration

Laws and Regulations on

drug administration

Laws and Regulationson Drug Registration


■■Other Normative DocumentsOther Normative Documents

Guidelines on Protection over TCM Products (2009)

Requirements on Biological Products

Requirements on File Management of APIs and Excipients

(will be implemented in 2010)

Provisions on Hospital Preparations (Interim)


Provisions on Drug Standards are being drafted and will be implemented in 2010.

Provisions on Drug Registration

15 Chapters and 177 Articles

Four Versions Provisions on New Drug Approval, implemented on May 1, 1999

Provisions on Drug Registration (interim), implemented on

December 1, 2002

Provisions on Drug Registration, implemented on May 1, 2005;

Provisions on Drug Registration, implemented on October 1, 2007.

Provisions on Drug RegistrationProvisions on Drug Registration

1.1. Supplementary Requirements on Registration of TCMsSupplementary Requirements on Registration of TCMs

(22 Articles)(22 Articles)

2.2. Requirements on On-Site Inspection for Drug RegistrationRequirements on On-Site Inspection for Drug Registration

(6 chapters and 55 articles)(6 chapters and 55 articles)

3.3. Requirements on Special Review and Approval for Drug Requirements on Special Review and Approval for Drug

RegistrationRegistration (22 Articles) (22 Articles)

4.4. Requirements on Registration of Technical Transfer of Requirements on Registration of Technical Transfer of

DrugsDrugs (4 chapters and 26 articles) (4 chapters and 26 articles)

Supplementary Documents for the Newly

Revised Provisions on Drug Registration

Improve laws and regulations on drug registration

Provide details related to core content of Provisions

on Drug Registration

Enhance practicability of the Provisions

Combine supervision and service

Supplementary Documents for the Newly Revised Provisions on Drug Registration

Requirements on Requirements on Special Review for Special Review for Drug RegistrationDrug Registration

Foundation

Forty-fifth article of Provisions on Drug Registration:

specific requirements on special review shall be drafted independently

General Principles and Objectives

Early intervention, prioritized review, multi-

channel communication, and real-time information updating

Strike a balance between promoting

innovation and controlling risksEncourage and support the development of

new drugs

Major Content

1 、 Adopt multiple measures to promote innovation

2 、 Enhance risk control to better regulate

Adopt multiple measures to promote innovation

1. Independent channel and prioritized review independent filing independent coding prioritized review limited timeframe


2. Convenient, scientific and reasonable access mechanism

If consistent with items 1 and 2 of the 45th article, start the procedures when submitting clinical application, and confirm within 5 working days

If consistent with items 3 and 4 of the 45th article, start the procedures when submitting production application, and organize expert review in 20 days

If included in special review when submitting clinical application, include directly in the procedures when submitting production application.


3. Timely intervention, and communication mechanism on key stages

Early communication time: before applying for clinical trials content ： application for special review,

key technical issues Specialized communication time ： during technical review and during

clinical trials content ： key security issues ， clinical

trial plan ， evaluation on phased clinical trials


4. Timely gather supplementary materials through multiple channels

On review conferences participated by applicants and experts

After meetings proposed by applicants For key security issues According to notices on supplementary

information Allow changes in clinical services to

improve efficiency Timeframe increased from 4 months

(for common application) to 8 months

Enhance risk control to better regulate

Make risk control plan when submitting application, and allow market entry upon meeting certain conditions.

Set up an exit mechanism for application for new drug registration special review

Establish a database for application for new drug registration special review to facilitate public supervision

Four Guidelines on Implementation1.Guidelines on Materials on Independent Filing of Products Subject to Special Review2. Guidelines on Communication Mechanism for Products Subject to Special Review3. Guidelines on Meeting Minutes for Special Review4. Guidelines on Information Release concerning Products Subject to Special Review

Progress of Implementation

Twenty-eight products have entered special review procedures, including 23 chemical drugs and 5 biological products.

Twenty-seven products are for APIs, finished products or biological products that have never been marketed in China or any foreign countries. (Article 2.2) One is for a new drug that has therapeutic advantages or there is no effective treatment for the diseases. (article 2.3)

Other 11 products which are evaluated according to the Requirements on Special Review and Approval are for drugs or vaccines for the treatment and prevention of H1N1.

Requirements on Registration Requirements on Registration of Technical Transfer of Drugsof Technical Transfer of Drugs

To Encourage the Innovation

To Promote the Concentration and Saving

To Open the Transfer Market

To Regulate the Registration

To Control the Risk

To Ensure the Quality

To Save the Cost

To Stimulate the Market

Requirements on Registration of Requirements on Registration of

Technical Transfer of DrugsTechnical Transfer of Drugs Key Point 1

To Encourage the Innovation

to encourage the combination of research and production, to promote the commercialization of research projects, to promote the introduction of foreign new technology and to show the strong commitment on the innovation.



To Promote the Concentration and Saving to encourage the good companies to carry

out asset restructuring, to rationally allocate the resources, to adjust the product structure, to update the technologic capacity and to make full use of the advantages, so as to promote the concentration of the entire industry.



To Open the Transfer Market

on the basis of new drug technical transfer, to enlarge the scope of transfer and allow the technical transfer for new drug prior to the expiry of monitoring period as well as the transfer of manufacturing technology after the expiry of monitoring period.



To regulate the Registration

to regulate the registration process between the two sides of the technical transfer by

setting up criteria on the qualification, technical standards and requirements. In the past, there was no need to carry out technical review and clinical validation before the technical transfer of the new drug , now things have been changed and the technical threshold has been improved.

TransfereeTransfereeBE study

Clinical Trial

Other study

Batch production

TransferorTransferor

Technical Review

Technical Review



To control the Risks to control the safety risks by three methods, including dynamic

control, static control and procedure control. Static Control: high risk products are not applicable for technical

transfer;

Dynamic Control: Where high risks are newly discovered, the

technical transfer shall be ceased.

Procedure Control: where safety risks are discovered during the

process of technical review, the technical transfer shall not be

approved.



To Ensure the Quality with the strict technical review and the

validation research carried out by the enterprises, the quality of the products before and after the transfer shall be consistent.



To Save the Cost

The companies are able to gain the license by technical transfer, not by changing dosage forms or applying for generic drugs. By these means, the cost on research and development as well as timing could be saved, the low-level redundant production can also be reduced. The one-one transfer may also enable us to control the total number of drug approval licenses.



To Stimulate the Market

The enterprises can restructure their assets by implementing technical transfer. The market of pharmaceutical technology could be promoted and the merger and cooperation could also be encouraged.


To regulate the drug research activities and to promote the level of drug

research;

The introduction of ICH guidelines;

To deal with the global drug research and to promote the mutual recognition

on drug registration as well as the standard harmonization;

To improve the requirements on drug safety by considering the new

problems discovered during the daily regulation.


Formally promulgated: 80

chemical drugs: 31 (the Technical Guidelines on Drug Carcinogenicity Study will be issued soon.)

TCMs: 12

Biological Products: 26

General Subjects: 6

General Principles: 5


Asking for Comments

Chemical Drugs: 4

TCMs: 1


Cases： taking the problems detected by regulation into consideration, SFDA

issued some technical requirements and guidelines into consideration

since 2008 in order to improve the requirements on drug safety.

Basic Technical Requirements on Injections

Basic Technical Requirements on Multi-Compound Bio-Chemical

Injections

Technical Guidelines on the Research on Changes of Marketed

Chemical Drugs

Technical Guidelines on the Research on Changes of Marketed

TCMs.

Major Measures adopted on Drug Registration

To regulate the on-site inspection for drug registration;

To carry out the evaluation on the implementation of GCP;

To initiate the review process on drug re-registration; To stick to the science-based evaluation and to

strengthen the control of risks; To use all kinds of methods to ensure transparency; To rationally allocate the resources and to improve the

efficiency of technical review.

To regulate on-site inspection for drug registration

In order to unify the standards and procedures, the provincial Food and Drug Administrations have developed the following documents for the on-site inspection for drug registration:

—implementation guidelines and working procedures

—SOPs and other requirements for inspectors

In 31 provinces of China, we have carried out 3721 on-site inspections for drug registration, among them, 1133 are for new drug applications, 1198 are for generic drug applications and 1390 are for the application on changes.

To carry out the evaluation on the implementation of GCP

To carry out the re-check on GCP clinical research institutes

To carry out on-site inspection on the clinical trials of imported drugs and to evaluate the implementation of GCP.

To initiate the review process on drug

re-registration Every province has developed a work plan

for re-registration; 3028 products got re-registered throughout

China.

To stick to the science-based evaluation and to strengthen the

control of risks To carry out the research on the CTD of generic

chemical drugs; To develop and implement the Technical

Guidelines on Drug Carcinogenicity Study; To adopt the third party validation in order to

ensure a reliable and scientific review result; To hold the specific seminars and consultations in

order to solve the common problems during the technical review, to unify the review standards and to ensure the consistency of the review result.

To use all kinds of methods to ensure transparency

To make almost 70 review cases public; To have communication with the applicants by expert consultation,

consultation meeting, video conference, teleconference, etc. When reviewing the H1N1 vaccines, technical review was organized

in a public way. The principles of public votes and public involvement were introduced in order to ensure the safety and efficacy of vaccines as well as the transparent and opened evaluation.

To use different methods such as consultation day, opening day, mailbox of the director general in order to strengthen the communication with the society, to promote the openness and transparency of technical review and to establish a “sunshine” review gradually.

Methods Introduced in 2009 to Ensure the Openness and Transparency of the

Technical Review

Methods Amount Methods Amount1.Public Review When reviewing the

H1N1 vaccines, technical review was organized in a public way and the votes were made on the spot.

6.Video Conferences 10

2.To publicize the review cases

To publicize almost 70 cases and their analysis on the website.

7.Seminars 14 seminars with 4000 participants.

3.Openning Day 11 times, 281 people. 8.Consultation Meetings (communication meetings)

80

4.Consultation Day 4000 people 9.Experts’ consultation 11 consultation related to 282 drugs.

5. Information release Answer 1600 questions

To Initiate the Special Procedure and to Ensure

the Disease Prevention and Control

In order to deal with emergencies, SFDA issued the following documents:

Notice on the Preparation of H1N1 Vaccine Production Work Plan on the Special Review and Approval for H1N1

Vaccines Work Plan on the Review and Approval of H1N1 Vaccines Key Items on the Research and Development of H1N1 Vaccines Notice on Strengthening the Regulation on Research and

Development of H1N1 Vaccines Notice on the On-Site Inspection for the H1N1 Vaccine Samples

for Clinical Trials. Notice on Issuing the Approval License for H1N1 Vaccines

To Initiate the Special Procedure and to Ensure

the Disease Prevention and Control

To approve 10 H1N1 vaccines for marketing;

To approve the importation of Zanamavir Powders;

To approve the enlarged production and changed manufacturing process of Phosphate Oseltamivir.

To Promote the IT System on Drug Registration

The NDRC approved SFDA’s proposal on Phase I IT System on Drug Regulation on September 30, 2009.

The Department of Drug Registration established the IT system on the Insert Sheet and Labeling of Drugs and initiated the testing program on that system.

IT systems to be established in 2010 ： IT system on the Filing of APIs and Excipients. IT system on the Drug Standards Management

Data Analysis on Statistics of Drug Registration in 2009

Market Approval in 2009

Type of Medicines

Concentrated Review Regular Review

Chemicals 834 548TCMs 1474 92Biological Products / 38

Imported Drugs

/ 114

Total 2308 792Total 3100

Drug Registration Approval in 2009

The Drug Approvals Made in Accordance with the Newly Revised Provisions on Drug

Registration

Registration Type

Approval for domestic productionApproval for ImportationNew Drugs

Changed Dosage Forms

Generics Total

Chemical Drugs

175 17 356 548 100

TCMs 72 8 12 92 1

Biological Products

38 38 13

Total 678 114

Total 792

The Drug Approvals made in accordance with the newly revised Provisions on Drug Registration in 2009

Registration Type

Class 1

Class2

Class 3

Class4

Class 5

Class6

Chemical Drugs

13inc：1.1, 2；1.3, 2；1.5, 6，Original Class I, 3

20inc：2, 1Original class II, 19

95inc：3.1,69；3.2,18；3.3,4；3.4,2；Original Class III, 2

47inc：4, 14；Original Class IV, 33

/ /

TCMs

2 70Inc:6, 65；Original Class VI,5

Various Categories of Domestic New Drugs approved in 2009

NOTE: Calculated according to Number of Receiving and Acceptence.

Approvals for Chemical Drugs Approvals for TCMs

New Drugs


GenericsNew

Drugs


Generics

Compounds or Prescriptions

94 16 142 72 8 12

Number of Receiving and

Acceptance175 17 356 65 8 11

Ration 1:1.9 1:1.1 1:2.5 1:1.1 1:1 1:1

Ratio of the Compounds or TCM preparations and the Number of Receiving and Acceptance

This ration can show the status of repeated application. The statistics show that the ration of chemical compounds for new drugs and the number of receiving and acceptance is 1:1.9, for the changed dosage forms, 1: 1.1, for generics, 1:2.5, much lower than the ration in 2008 (1:2.5 for new drugs and 1:3 for generics). While for the approval for TCMs, it shows that there is no repeated applications for TCMs.

Comparative Analysis on Application Items

Approvals for Chemical Drugs

Approval for TCMs

New Drugs


GenericsNew

Drugs


Generics

Number of Receiving and

Acceptance175 17 356 72 8 12

Proportions 32% 3% 65% 78% 9% 13%

Rations of Different Application Items Calculated according to the Numbers of Receiving and Acceptance.

The Ration of New Drugs reflects the status of drug research, review structure and tendency. The annual statistics (calculated according to the number of receiving and acceptance) shows that the new chemical drugs accounts for 32% of the total approval, while for changed dosage forms, 3%, for generics, 65%. For TCMs, the proportion is 78%, 9% and 13% （ see the form above). While for the year 2006 and 2007, the ration of new drug is no higher than 15% and the changed dosage forms and generics accounts for more than 80%.)

Statistics on Receiving and Acceptance in Recent Five

Years

Testing on the Imported Drugs

Categories Total Batches Tested

Imported Batches

Total Sum Imported （Billion US dollars）

Disqualified Batches

Chemical Drugs

21451 21400 80.4 51

TCMs 2410 2393 2.4 17

Biologics 1375 1375 13.5 0

Total 25236 25168 96.4 68

Imported Drug Testing in 2009

In 2009, 25236 batches (9.64 US dollars) imported drugs were tested and 25168 batches were qualified and 68 batches were disqualified.

Testing on Imported Drugs

Number of Unqualified Batches

26

7 64 3 2 2 2 1 1 1 1 1 1

0

5

10

15

20

25

30

H1 Y D F X1 L J S X2 R1 R2 M K H2

* Calculated according to the disqualified batches

Testing on Imported Drugs

Value of unqualified drugs（10,000 dollars）

050

100150200250300350400450500

F H1 X1 S Y M R1 D J K X2 L R2 H2

Data Analysis on Drug Registration Approvals in 2009

The numbers of applications returns to normal;

The repeated applications were reduced; Rational application structure reached and

remained.

Statistics on Pharmaceutical Industry in 2009

The Rapid Development of Chinese Pharmaceutical Industry in spite of

Depression

The Increase of Chinese Pharmaceutical Industry in

2009CategoryM Output （ 100

million RMB）Increase Ratio（ %）

APIs 1837.5 13.7

Finished Chemical Drugs

2758.6 19.0

TCMs 1998.0 24.0

Processed Slices 511.7 28.3

Bio-chemicals 887.2 29.1

Medical Equipments and Devices

950.0 22.9

Hygiene Materials and Medicinal Products

520.7 29.0

Total 9915.9 21.4

Opportunities for the Development of Chinese Pharmaceutical

Industry

Policy Factors that may Affect the Pharmaceutical Industry in

2010In 2009, there are many policies related to medicines were promulgated.

In April, 2009, the new plan on medical reform was issued; In May, the Comments on the Promotion of TCM Industry was

issued; In June, the Comments on the Promotion of Biologic Products

Industry was issued; The List of Essential Medicines and the List on Medical Insurance.

——These policies have greatly stimulated the demand for medicines and the industry tended to move towards the local and village level. The concentration of the industry was encouraged and the market became larger and larger.

From 2009 to 2013, it is estimated that 17countries will boast the increase of total sale of medicines, which accounts for 90 billion US dollars and accounts for 48% of the total increase throughout the world. While in 2009, the proportion is 37%.

The great changes on the world economy, the development of health industry (improvement of medical service and increased investment), and the changed proportion between generics and innovative drugs have led to the adjustment of the market.

Anticipation of the Future Chinese Pharmaceutical Industry

In 2011, China will become the third biggest market for pharmaceuticals in the World.

Root causes of problems in pharmaceutical industry have not been resolved

Large number of small businesses and low industrial concentration

Insufficient R&D investment, low innovation ability, low proportion of high-tech products

Gap between international and domestic quality control systems and practices

Drug quality and safety incidents Lack of fair and orderly market to ensure survival

of the best low competitiveness of low value-added exported

products

Outstanding problems in pharmaceutical industry

The extensive growth mode: high input, high consumption, high pollution, high

emissions, low efficiency, low concentration and low technological level

Export volume of 2009 was 19.2 billion USD, of which 16.6 billion was raw materials, accounting for 86.24%; medicine, 1.2 billion; and biological durgs, 1.45 billion.

1299 companies which produce western medicines exported their products, including 181 foreign-fuded enterprises, accounting for 14%. However the proportion of exports accounted for 51.92%

Conclusion

In spite of the background of financial crisis, the pharmaceutical industry in China has increased and the increasing rate is higher than the common ratio of the other industry sectors.

In 2009, the strengthened legal system of drug registration as well as other important activities had greatly promoted the healthy development of Chinese pharmaceutical Industry.

International Exchanges in 2009

International Cooperation Programs related to Drug Registration in 2009

1. Meeting with Senior Delegation of PHAMA and BIO （ April, 2009, Changsha ）2. Training on GCP Inspection with RDPAC/FDA (June 11 to 14, 2009, Beijing)3. Training on GLP Inspection with RDPAC/FDA (Sept.10 to 13, 2009, Hangzhou)4. Meeting with Mr. Kasoff, Deputy Assistant Minister of US DOC, (Sept. 2009,

Beijing)5. JCCT Seminar on Data Protection (Sept. 2009, Beijing)6. JCCT Seminar on Anti-Counterfeiting Drugs (Nov. 2009, Beijing)7. Seminar on Generic Biologic Products with BIO (Nov.5, 2009, Beijing)8. The First DIA China Conference, (Nov. 1 to 3, 2009)9. Sino-Korea-Japan Seminars on Clinical Trials (Dec.17, 2009, Beijing)10. The First Meeting of China ICH Research Group, (Dec.2009, Beijing)11. The Second Meeting of China ICH Research Group, (April, 2010, Beijing)12. International Seminar on Marketing Licenses with RDPAC (March, 2010, Beijing)13. Seminar on the Clinical Trial Supervision of Biologic Products with BIO (March

24, 2010, Beijing)

Progress on the Anti-Counterfeiting Drugs in 2009

The effectiveness of the joint fight against counterfeit medicines of china’s 13

ministries Joint conference system for inter-ministerial coordination to combat sales of counterfeit drugs was set up in April

Three joint committee, one coordinators meeting, and a national television and telephone conference were held

546 illicit networks were closed(MITT) 323 registered cases, of which 320 were solved(Ministry of Public Security) A number of major and serious criminal cases of more than 10 million were

uncovered More than 6000 pieces of illegal medical advertisements were investigated,

fined 40 million yuan;16,000 cases of illegal advertisers were investigated, a fine of more than 60 million. Ordered to stop publishing more than 20,000 unlawful “sex drugs” ad(Trade and industry Bureau)

30 people in broadcast organizations have been dealt with (Radio Division) 606 times administrative compulsory measures to suspend false medical

advertisements on illegal sales, revocation of 44 pharmacy license number, recovery or write-off of 12 health food approval number. Three “internet consumers in the safety alert bulletin” and one illegal drugs, medical devices notice were released, 75 illegal businesses were exposed

Joint Mechanism on Anti-Counterfeiting Activities among 13 Ministries in China

Objective: to solve the difficult problem that one single agency cannot deal with counterfeiting alone.

Ministry of Public Security, to strengthen the supervision

of cases by referring the Jurisdiction Explanations

State Post Office:To strengthen the

regulation on mailbox rent and posted drugs

SFDA, to make full use of

the joint mechanism

Ministry of Information Industry:

To supervise the information on the internet

SAIC: to strengthen the

regulation on drug advertisement

The Working Procedure on Joint Mechanism: the Joint Conference on Combat on Counterfeiting Drugs and the Functions of the Members of Joint Conference on Combat on Counterfeiting Drugs.

For the combat on counterfeiting drugs distributed through internet or post system: Notice of the Specific Rectification Campaigns on Fraudulent Advertisement or Distribution through Post System and the Implementation Plan.

Big Cases (over 10 million RMB) Li Bin Case on April 14 BOZHOU Case on July 19 SUINING Case (counterfeiting drugs through post system) YANTAI Case HUZHOU Changxing Website Case GUANGZHOU Case YANCHENG Case on Internet Sale of Counterfeiting Drugs

Documents Issued by Members of the Joint Mechanism

Thank you very much!Thank you very much!

ZHANG WEI Director General, Department of Drug Registration May 17, 2010, Beijing

Documents

Transcript of ZHANG WEI Director General, Department of Drug Registration May 17, 2010, Beijing