Churchill, Winston Expectations are same: Safety Efficicacy GMP - - PowerPoint PPT Presentation

“The pessimist sees difficulty in every opportunity, the optimist sees the opportunity in every difficulty”.

Churchill, Winston

Expectations are same:

 Safety  Efficicacy  GMP compliance

Profile attribute Population GDP growth GDP per capita Public expenditure

• n health

Private expenditure

• n health

2003 1.293 B Bln USD 4,157.8 USD $3217 1.6% of GDP 3.0% 2009 1.341B Bln USD 10,085.7 USD $7519 2.4% of GDP 2.2%

Profile attribute Import of goods Import of goods and service Export of goods Export of goods and service 2003

• Bln. US$

412.8 27.4%

• f GDP
• Bln. US$

438.2 29.6% 2010 Bln. US$ 1396.0 22.3%

• f GDP

Bln. US$ 1577.8 26.7%

 Total value 1252.3 Billion RMB  Annual increase 21.3% during 10th 5 year plan  above GDP and national average level

section value billion chemicals 240.58 Preparations 354.69 TCM 335.91 Biological Products 131.42 Medical Products 189.62

Q2 2012 CNY 405 B. = 21.1% growth Q1 2012 24.1% growth

 2012 growth rate significantly higher than Q1 and Q2

• f 2011

 12m MAT (moving annual total) 19.6% growth rate

compared with 18.3% in MAT Q2 2011

Hospital (100 beds or more) sales at hospital purchasing price

Domestic Application Reception

Foreign Application Reception Chemical Chinese Biologic Supplemental

Quantity 1528 105 69 2433 599 Sum 4135 2433 599 Total 4734

category 2008 2009 2010 2011 2011 renewal approvals Chemicals 2449 1587 1003 717 581 TCM’s 1160 1706 151 143 55 Biologicals 132 67 24 38 24 Total 3741 3360 1178 898 660

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

103 51 640 12 59 9 9 1 2 794 80 12 886

Type Domestic Foreign Total Chemicals 466 255 976 TCM 33 3 36 Biological 29 50 79 Total 528 308 1091

 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 1999

 1992: US-China MOU  1993:Provisions for Drug Administrative Protection were

enacted, 7.5 years of market exclusivity for patented drugs

 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

 The State Food and Drug Administration (SFDA), primarily

• versees 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.

 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

 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.

 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.

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

 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

 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)

 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”

 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

 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%)

 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

• n 18-24 subjects

 Generic drugs based on TCM or natural drug injections CT

• n not less than 100 pairs of cases are required

 Biosimilars subject to full phase III CT

 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

Article 11:

 Applicant to submit documents explaining the China

Patent Status and ownership rights. Assume liability

• f 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

 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

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, non-

infringement 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

 Application to be filed with the provincial FDA (PFDA)  PFDA determines whether application dossier is in proper

• rder

 PFDA provides notification of acceptance or reasons for

rejection and opportunity to reapply

 Within 5 days of acceptance, the PFDA will conduct an on-

site 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

 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)

 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

• r approval of generic drug application

 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 2015-2020

 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

MAA specified in certificate of pharmaceutical product (CPP) can be holder and applicant of IDL Fees CNY 45300+ CNY 50000 (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

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 multi-

jurisdictional filing 2002:

 Adopted data exclusivity for 6 years term  Added provisions on patent linkage

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

 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

 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