The pessimist sees difficulty in every opportunity, the optimist sees the opportunity in every difficulty. Churchill, Winston

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2 The pessimist sees difficulty in every opportunity, the optimist sees the opportunity in every difficulty. Churchill, Winston

3 Expectations are same: Safety Efficicacy GMP compliance

4 Profile attribute Population GDP growth GDP per capita Public expenditure on health Private expenditure on health B Bln USD 4,157.8 USD $ % of GDP 3.0% B Bln USD 10,085.7 USD $ % of GDP 2.2%

5 Profile attribute Import of goods Import of goods and service Export of goods Export of goods and service 2003 Bln. US$ % of GDP Bln. US$ % 2010 Bln. US$ % of GDP Bln. US$ %

6 Total value Billion RMB Annual increase 21.3% during 10 th 5 year plan above GDP and national average level section value billion chemicals Preparations TCM Biological Products Medical Products

7 Q Q CNY 405 B. = 21.1% growth 24.1% growth 2012 growth rate significantly higher than Q1 and Q2 of m MAT (moving annual total) 19.6% growth rate compared with 18.3% in MAT Q Hospital (100 beds or more) sales at hospital purchasing price

8 Domestic Application Reception Chemical Chinese Biologic Supplemental Foreign Application Reception Quantity Sum Total 4734

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10 category renewal approvals Chemicals TCM s Biologicals Total

11 Approved Drugs in 2010 Chemical Drugs Chinese Medicines Biologics New drug Form changed drug Generic drug New drug Form changed drug Generic drug New drug Form changed drug Generic drug

12 Type Domestic Foreign Total Chemicals TCM Biological Total

13 1963: Chinese MoH planned drug regulation to manage 1979: MoH and State Pharmaceutical Admn jointly published the New Drug Management Regulation 1985: first comprehensive Drug Admn. Law 1988: rule for new importation drug registration; provisions were enacted in 1991 and revised : US-China MOU 1993:Provisions for Drug Administrative Protection were enacted, 7.5 years of market exclusivity for patented drugs

14 1999: The State Pharmaceutical Admn of China: division of Drug Admn in the MoH and the Division of TCM Admn Bureau were merged 2001: Drug Admn. Law revised; requires premarket testing and approval and prohibit drug adulteration Amendment 1; provision for New Drug Approval; Amendment 2; provision for new Biological Drug Approval 2001: Gained membership with WTO 2002: New Drug Registration Regulation aligned with WTO

15 The State Food and Drug Administration (SFDA), primarily oversees drug administration Used to be an independent authority but in 2008 incorporated into MoH because of drug safety and internal corruption scandals Centre for drug Evaluation (CDE) National Institute for the control of Pharmaceutical and Biological products (NICPBP) The State Development and Reform Commission (SDRC), responsible for the drug price administration; and The Provincial Administration for Industry and Commerce, cooperating with the Provincial Food and Drug Administration, (PFDA) to regulate drug advertisements.

16 Food and drug safety Basic healthcare system Perfect drug supply and guarantee system Guidelines for accelerating structure adjustment of pharmaceutical industry jointly issued by MIIT, MOH, and SFDA on Oct.9,2010 Guidelines and basic principles were provided

17 Incentives for 2012 GMP implementation Standards and timeline will not change Accelerating review and approval tech and transfers among subsidiaries and M&A deals Higher tender price for better products with 2010 GMP certifications Accelerated GMP certifications of facilities with international compliance certifications Research program listed as state major R&D projects will be reviewed through green channel Encourage short supply and orphan drugs mfg.

18 Multilateral cooperation: WHO, ICH, APEC, DCVRN, FHH, IRCH and PIC/S Bilateral cooperation: signed MOU with USA, Canada, Cuba, Brazil, Australia, EU, Russia, UK, France, Denmark, Italy, Latvia, Pakistan, Singapore, South Korea, Japan and Thailand etc.

19 ICH Chinese focus study teams: Formulated work specifications Regular work meeting Positive advancements: Publication of the translated version of ICH guidelines Established research achievement online disc 2010 annual report Complete logo design of ICH Chinese team Expanded study team size WHO vaccine pre-authentication System authentication

20 Signed negotiation cooperation mechanism with EC s DG Enterprise and Industry in Oct.2007 First annual high level working group meeting between SFDA and EU was in Bejing in April 2009 Commissioner Mr. John Dalli visited China and both parties renewed MOU in Oct.2010

21 In August 2007, US FDA Commissioner visited SFDA In Dec.2007 signed safety agreement of Pharmaceuticals and Medical Devices with DHHS of USA In Dec.2010 annual Sino-USA pharmaceutical regulatory meeting was organized and discussed mutual points of interest and collaboration FDA exchanges Generic Drug Forum Annual meeting and conferences (BIO Chinese and JCCT framework)

22 New Drug Application Drug standardized by the State (ANDA/ANDS) Import Drug Application Supplementary Application New Drug never been marketed in China Old regulation; produced in China for the first time Chinese manufacturer who produce imported drugs on Chinese market should submit the application accordingly to the requirements for the drug standardized by the State

23 Class 1: NCE s are true NCE that have not been marketed in the world Class 2: NCE s marketed abroad but not part of foreign pharmacopoeia and have not been imported to China Class 3: new combinations of already approved drugs Class 4: NCE s listed in foreign pharmacopoeia or previously imported into China; new dosage forms of approved drugs; new route of administration of approved drugs Class 5: New indications for approved NCE s

24 China accounts for 20% of world s population and only 1.5% of global drug market World s third largest prescription drug market and likely to grow for sometime Basic health insurance is not available for all therefore low cost and ability to cost effectively follow innovations Currently has about 4000 drug companies and most focused on generic business 2010 SFDA approved 886 applications and 651 were generics (73%)

25 No branded drug concept like in USA Amended regulation for drug registration uses new drugs that has not been previously marketed in China. Generic drugs has an existing national drug standard and was previously approved by SFDA Generic chemical drugs need BE studies to be conducted on subjects Generic drugs based on TCM or natural drug injections CT on not less than 100 pairs of cases are required Biosimilars subject to full phase III CT

26 Establish Regulations: measures for drug research supervision and management Establish Systems: scientific registration management system with technical review, audit, inspection etc. Establish the teams: internationalized professional inspector teams Establish the mechanisms: uniform, coordinated, flexible efficient dynamic audit and inspection mechanisms Establish the institution: grading and classification management institution for drug R&D units, CT, contract study and registration applicants and commissioners

27 Article 11: Applicant to submit documents explaining the China Patent Status and ownership rights. Assume liability of patent infringement Article 12: If an infringement dispute occurs after the registration parties negotiate or resolve through judicial organs to patent admn institutions Article 13: Under patent protection another sponsor can apply for registration within 2 years prior to expiry

28 Current Provision was promulgated on Oct.30, 2002 Put into force on Dec.1, 2002 More reasonable and suitable, particularly with regard to China s entry into WTO Qualification of the applicant has been clearly stipulated Applicant should be a legal entity such as corporation, pharmaceutical firm, government agency and/or scientific institution Import drug registration require branch in China or China s authorized agency Assigned person should have sufficient knowledge and proficient in admns of regulations

29 China s membership in WTO: Within 6 years of approval of drug with NCE the regulatory authority will not approve use of proprietary data to apply for NCE Required to submit patent information, ownership, noninfringement and promise to assume all the infringement responsibilities Allowed to submit within 2 years of patent deadline so as to allow to be in market immediately after patent expiry

30 Application to be filed with the provincial FDA (PFDA) PFDA determines whether application dossier is in proper order PFDA provides notification of acceptance or reasons for rejection and opportunity to reapply Within 5 days of acceptance, the PFDA will conduct an onsite inspection and take samples of 3 consecutive batches to send to Drug Control Institute for inspection PFDA will submit the dossier with its examination recommendation, verification report, results of inspection to the SFDA CDE within 30 days

31 CDE will organize pharmaceutical, medical and other technical staff to examine the application dossier and verification recommendations May request supplemental information if necessary Drug control institute provide the sample test report to the CDE. PFDA and the sponsor (30 days) CDE prepares a general examination recommendation and submit to SFDA along with the related data (160 days) SFDA makes the approval decision and issue a Drug Approval Number (if no CT needed) or Clinical Trials approval (10 days)

32 Applicant to submit the CT data to CDE for final approval CDE conduct technical examination of CT report SFDA makes approval decision based upon technical examination recommendations. (30 days) Issue DAN and Notification of Approval Opinion (10 days) Time to approval 205/245 working days (50 weeks) provided everything move as planned For drugs not meeting safety requirements the Amended Regulation grants SFDA authority to suspend acceptance or approval of generic drug application

33 wide quality and efficiency gaps existed before 2007 BE studies for such products in next 5-10 years Level of generic drugs to raise to international standards Start with essential drugs and commonly used drugs Initiatives will begin with essential drugs with large population, high consumption volume, multiple mfg. Oral drugs first and later on injectables BE guidelines and product selection RLD identification All required studies to be fully initiated by 2014 Injectable and other dosages from

34 SFDA and Guangdong provincial government joined to develop capacities on experimental basis MOU signed in March 2012 reform exploration and trial for drug evaluation and approval system To organize technical evaluation and approve new drugs tech transfer and drug production TT application Decisions will be filed with SFDA and SFDA will issue drug approval numbers Review and approve for CMO except TCM and biologicals

35 MAA specified in certificate of pharmaceutical product (CPP) can be holder and applicant of IDL Fees CNY CNY (sample testing) Clinical trials may be required for registration and may cost to the order of US$ 4-5 millions IDL application dossier is accepted Centre for drug evaluation (CDE) will issue a deficiency letter within 160 working days Applicant will have 4 months to prepare and submit the supplementary data required CDE will send its evaluation report to the SFDA within 54 working days The SFDA will issue the final decision within 25 working days Total 359 days or 71 weeks

36 Intellectual property environment 1993: Patent law to include API rather than process only Invention protection term from 15 to 20 years Joined the Patent Cooperation Treaty to allow multijurisdictional filing 2002: Adopted data exclusivity for 6 years term Added provisions on patent linkage

37 The system institution and legislation construction of drug registration management can not be fully adaptable to the demand of the new drug innovative production and industrial development changes in China The relevant management regulation in the drug R&D field (especially to CT) are still to be completed and the complete system still needs to be constructed for technical guidance principles The whole-process supervision and inspection system of drug registration is not complete, and there is a lack of professional and full time inspection teams, shortage of admn resources while continuous increase of supervision and management demands The risk control capacity in the drug R&D and registration process is insufficient capacity of communicate and supervise before, during and after study to be improved; excessive emphasis on post hoc supervision and management does not resolve the earlier croped issues

38 Generic IDL applications with clinical data, CDE will need another 90 working days to evaluate the dossier Certificate of good sales practice (CGSP) is required to distribute and sell pharmaceuticals in China Should have an inspected warehouse (at least 500 sm), registered pharmacists and documentation system Small agent employ the CGSP to do the business but it is prohibited by the SFDA Generic name should be in national s reimbursement drug list (NRLD) Ministry of Human Resources and Social Security updates the list every 4 years

39 National Development and Reform Commission (NDRC) controls the retail price of drugs listed under NRDL Exceptional retail price approval if proven that quality, safety and efficacy are better Such sponsors have little competition and higher margin to support their promotion campaign Agents can be blacklisted by the hospitals if they can not provide according to the signed agreement Often use money promotion rather than academic detailing. Illegal step and getting legal actions Annual pharmacovigilance report so as to re-register after 5 years

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