ASSURING QUALITY FROM DEVELOPMENT TO PATIENT or Managing

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ASSURING QUALITY FROM DEVELOPMENT TO PATIENT or “Managing the Risk” Gerald W Heddell Director,

ASSURING QUALITY FROM DEVELOPMENT TO PATIENT or “Managing the Risk” Gerald W Heddell Director, Inspection, Enforcement and Standards Division Medicines & Healthcare products Regulatory Agency May 2011 Gerald W Heddell – Managing the Risk – DIA China, May 2011 1 ©

Crown copyright 2011 The materials featured within these MHRA presentation notes and delegate pack

Crown copyright 2011 The materials featured within these MHRA presentation notes and delegate pack are subject to Crown copyright protection for this event. Any other copy or use of Crown copyright materials featured in this presentation, in any form or medium, is subject to prior approval of the MHRA which has Delegated Authority from Her Majesty's Stationery Office (HMSO) to administer Crown copyright for MHRA originated material. Applications should be in writing, clearly stating the proposed use/reuse of the information, and should be sent to the MHRA at the following address: Conference and Education Function, 4 th floor, 151 Buckingham Palace Road, Victoria, London SW 1 S 9 SZ. Tel: 0203 080 6930 or e-mail speakers@mhra. gsi. gov. uk. You may not sell or resell any information reproduced to any third party without prior agreement. The permission to reproduce Crown copyright protected material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned. Gerald W Heddell – Managing the Risk – DIA China, May 2011 2 ©

Content - Managing risk - Lessons from history - Regulatory processes Assessment Inspection Surveillance

Content - Managing risk - Lessons from history - Regulatory processes Assessment Inspection Surveillance - Conclusions Gerald W Heddell – Managing the Risk – DIA China, May 2011 3 ©

What is risk? Gerald W Heddell – Managing the Risk – DIA China, May

What is risk? Gerald W Heddell – Managing the Risk – DIA China, May 2011 4 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 5 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 5 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 6 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 6 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 7 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 7 ©

The Meaning of Life - for the MHRA Mission The MHRA’s mission is to

The Meaning of Life - for the MHRA Mission The MHRA’s mission is to enhance and safeguard the health of the public by ensuring that medicines and medical devices work, work and are acceptably safe Gerald W Heddell – Managing the Risk – DIA China, May 2011 8 ©

“If you do not manage risk, it will manage you? ” Gerald W Heddell

“If you do not manage risk, it will manage you? ” Gerald W Heddell – Managing the Risk – DIA China, May 2011 9 ©

The History of Pharmaceuticals is a great success story But also a catalogue of

The History of Pharmaceuticals is a great success story But also a catalogue of disasters! Gerald W Heddell – Managing the Risk – DIA China, May 2011 10 ©

UK Therapeutic Substances Act (1925) Reporting of Adverse Events Gerald W Heddell – Managing

UK Therapeutic Substances Act (1925) Reporting of Adverse Events Gerald W Heddell – Managing the Risk – DIA China, May 2011 11 ©

US Federal Food, Drug and Cosmetic Act (1938) Stricter controls on labelling, safety and

US Federal Food, Drug and Cosmetic Act (1938) Stricter controls on labelling, safety and listing Gerald W Heddell – Managing the Risk – DIA China, May 2011 12 ©

Nuremburg Code (1947) Protection of trial subjects Gerald W Heddell – Managing the Risk

Nuremburg Code (1947) Protection of trial subjects Gerald W Heddell – Managing the Risk – DIA China, May 2011 13 ©

UK Medicines Act 1968 Gerald W Heddell – Managing the Risk – DIA China,

UK Medicines Act 1968 Gerald W Heddell – Managing the Risk – DIA China, May 2011 14 ©

Phase 1 Accreditation for Clinical Trials Gerald W Heddell – Managing the Risk –

Phase 1 Accreditation for Clinical Trials Gerald W Heddell – Managing the Risk – DIA China, May 2011 15 ©

METHOTREXATE, CHINA • over 100 paralysed • vincristine contamination Gerald W Heddell – Managing

METHOTREXATE, CHINA • over 100 paralysed • vincristine contamination Gerald W Heddell – Managing the Risk – DIA China, May 2011 16 ©

HEPARIN, USA • 100 deaths • 1000 serious adverse reactions • hypotension and allergic

HEPARIN, USA • 100 deaths • 1000 serious adverse reactions • hypotension and allergic reactions • intravascular use of unfractionated Heparin • Chinese source • Up to 50% over sulphated chondroitin sulphate (OSCS) • Product recalled Gerald W Heddell – Managing the Risk – DIA China, May 2011 17 ©

HEPARIN, EU • no deaths • no ADR trends (except Germany) • US unfractionated

HEPARIN, EU • no deaths • no ADR trends (except Germany) • US unfractionated Heparin not supplied to Europe • crude Heparin supplied from China • low molecular weight Heparin contaminated with up to 7% OSCS • largely subcutaneous use • limited recall • restrictions to use Gerald W Heddell – Managing the Risk – DIA China, May 2011 18 ©

HEPARIN, OBVIOUS LESSONS • knowledge of supply chain • risk assessment and management •

HEPARIN, OBVIOUS LESSONS • knowledge of supply chain • risk assessment and management • product specification • involvement with suppliers Gerald W Heddell – Managing the Risk – DIA China, May 2011 19 ©

Pedigree in EU GMP QP declaration in EU MAs Gerald W Heddell – Managing

Pedigree in EU GMP QP declaration in EU MAs Gerald W Heddell – Managing the Risk – DIA China, May 2011 20 ©

Heparin Supply Chain (Pedigree) China Pig Mucosa China +8 +1 SITE sites site C

Heparin Supply Chain (Pedigree) China Pig Mucosa China +8 +1 SITE sites site C D E F +21 sites PIGS POLAND/ GERMANY PIGS SPAIN/ FRANCE GERMANY SPAIN PIGS FRANCE EXTRACTION Crude Heparin Sodium China SITE SITE A B C D E F CHINA GERMANY Broker PURIFICATION Pure Heparin Sodium (Ph Eur) Stating Material USA SPAIN NETHERLANDS FRANCE 7 STEPS Heparin sodium API Gerald W Heddell – Managing the Risk – DIA China, May 2011 SINGAPORE 21 ©

Supply Chain Pedigree ‘Family tree’ for the API Starting from the ‘critical starting materials’

Supply Chain Pedigree ‘Family tree’ for the API Starting from the ‘critical starting materials’ Including all players i. e. Intermediate manufacturers- propagators; abattoirs API manufacturers Micronisers Repackers and relabellers Brokers and traders Shippers Importers Gerald W Heddell – Managing the Risk – DIA China, May 2011 22 ©

Supply Chain Pedigree - GMP Guideline requirements - QP Declaration in MA dossier Also

Supply Chain Pedigree - GMP Guideline requirements - QP Declaration in MA dossier Also required by US Drug Safety and Accountability Act 2010 Gerald W Heddell – Managing the Risk – DIA China, May 2011 23 ©

Is it possible to overt risk before disaster happens? Gerald W Heddell – Managing

Is it possible to overt risk before disaster happens? Gerald W Heddell – Managing the Risk – DIA China, May 2011 24 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment MA CTA GLP > Inspection GCP GMP GDP > Surveillance GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 25 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 26 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 26 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment CTA MA GLP > Inspection GCP GMP GDP > Surveillance GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 27 ©

Clinical Trials – Approval and Good Clinical Practice Legal Framework: Directive 2001/20/EC transposed into

Clinical Trials – Approval and Good Clinical Practice Legal Framework: Directive 2001/20/EC transposed into national law Guidance Documents: ICH European Commission EMA National Gerald W Heddell – Managing the Risk – DIA China, May 2011 28 ©

Assessment of CT applications: National Member State responsibility, not at a European Lead Gerald

Assessment of CT applications: National Member State responsibility, not at a European Lead Gerald W Heddell – Managing the Risk – DIA China, May 2011 29 ©

European Clinical Trial Directive -Transposition into Member State legislation by May 2000 - Required

European Clinical Trial Directive -Transposition into Member State legislation by May 2000 - Required Commission Directives on GCP and GMP - Required detailed guidelines: Now in Volume 10 of Rules Governing Medicinal Products in the EU (Eudralex) (http: //ec. europa. eu/enterprise/pharmaceuticals) Gerald W Heddell – Managing the Risk – DIA China, May 2011 30 ©

GCP Directive 2005/28/EC of 8 th April 2005 - outlines GCP principles GMP Directive

GCP Directive 2005/28/EC of 8 th April 2005 - outlines GCP principles GMP Directive 2003/94/EC of 8 th October 2003 - GMP principles - Inspections - Quality Management Systems - Labelling Gerald W Heddell – Managing the Risk – DIA China, May 2011 31 ©

European Clinical Trials Directive - Aim of harmonising the rules for conducting trials Protecting

European Clinical Trials Directive - Aim of harmonising the rules for conducting trials Protecting rights, safety and well-being of participants in research - Aim to provide environment for clinical research, protect participants without hampering the discovery of new medicines Gerald W Heddell – Managing the Risk – DIA China, May 2011 32 ©

National Competent Authority (NCA) Timescales TOTAL TIME = 60 DAYS AUTHOR. Eudra. CT Number

National Competent Authority (NCA) Timescales TOTAL TIME = 60 DAYS AUTHOR. Eudra. CT Number No GNA No Yes GNA RESP APP 30 D Gerald W Heddell – Managing the Risk – DIA China, May 2011 14 D Yes REJECT 16 D 33 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment MA CTA GLP > Inspection GCP GMP GDP > Surveillance GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 34 ©

Marketing Authorisations § In order to be marketed in the UK, a medicinal product

Marketing Authorisations § In order to be marketed in the UK, a medicinal product requires a marketing authorisation. Definition of a medicinal product is set out in Directive 2001/83/EC, as amended (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. ’ § To obtain a marketing authorisation, a dossier of information to support the claims that the product is of adequate quality, is safe and that it works is submitted to the MHRA. § MHRA responsible for ensuring that medicines and medical devices work and are acceptably safe Gerald W Heddell – Managing the Risk – DIA China, May 2011 35 ©

The Common Technical Document (CTD) Admin Not part of the CTD MODULE 1 MODULE

The Common Technical Document (CTD) Admin Not part of the CTD MODULE 1 MODULE 2 Non-clinical Clinical overview Overview Quality overall summary Non-clinical summary Clinical summary Quality Non-clinical study reports Clinical study reports MODULE 3 MODULE 4 MODULE 5 Gerald W Heddell – Managing the Risk – DIA China, May 2011 The CTD 36 ©

The Assessment Process Assessors § Non-clinical assessors (toxicologists) § Quality (pharmaceutical) assessors § Clinical

The Assessment Process Assessors § Non-clinical assessors (toxicologists) § Quality (pharmaceutical) assessors § Clinical (medical) assessors § Statistical assessors The Assessment Report (AR) § Critical, concise analysis of the respective parts of the dossier with clear conclusions § Used to highlight key elements and critical issues for each application § Document in which assessors justify regulatory decisions. Gerald W Heddell – Managing the Risk – DIA China, May 2011 37 ©

Types of Application § New active substances § Existing active substances (abridged applications) Types

Types of Application § New active substances § Existing active substances (abridged applications) Types of Regulatory Procedure § National procedures § European procedures Centralised Procedure Mutual Recognition Procedure (MRP) De. Centralised Procedure (DCP) Gerald W Heddell – Managing the Risk – DIA China, May 2011 38 ©

Overview of Procedures (1) National Procedure § UK only § Follow internal targets for

Overview of Procedures (1) National Procedure § UK only § Follow internal targets for assessment § Less popular now § National variations Gerald W Heddell – Managing the Risk – DIA China, May 2011 39 ©

Overview of Procedures (2) Centralised Procedure § Effective from 1995 § Administered by EMA

Overview of Procedures (2) Centralised Procedure § Effective from 1995 § Administered by EMA (European Medicines Agency) § CHMP (Commission on Human Medicinal Products) delivers opinion § Assessment by Rapporteur and Co-rapporteur § Decision accepted by all § Single Community authorisation granted by EC § Mandatory use or. . § Optional use Gerald W Heddell – Managing the Risk – DIA China, May 2011 40 ©

Overview of Procedures (3) Mutual Recognition Procedure (MRP) § Effective from January 1998 §

Overview of Procedures (3) Mutual Recognition Procedure (MRP) § Effective from January 1998 § Requires an MA in one member state (Reference Member State: RMS) § Applicant chooses Member States (Concerned Member States: CMS) § RMS updates assessment report § Report circulated to CMS, Applicant and EMEA § 90 day procedure resulting in mutual recognition and harmonisation § Repeat use § Variations follow MR procedures § Outgoing MR (UK is RMS) or Incoming MR (UK is CMS) Gerald W Heddell – Managing the Risk – DIA China, May 2011 41 ©

Overview of Procedures (4) De. Centralised Procedure (DCP) § § § § § Introduced

Overview of Procedures (4) De. Centralised Procedure (DCP) § § § § § Introduced in the 2001 review of medicines legislation (2004/27/EC), effective in the UK from 30 October 2005 Product has no MA at the time of application Application chooses RMS and CMS Parallel assessment of identical dossier by RMS and CMS RMS circulates assessment report at day 70 210 day procedure resulting in harmonisation of SPC, labelling and leaflet (www. hma. eu/92. html) Two steps of assessment No consensus reached or withdrawal in step II: Referral to CMD(h) Variations follow MR timelines Gerald W Heddell – Managing the Risk – DIA China, May 2011 42 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment MA CTA > Inspection GLP GCP GMP GDP > Surveillance GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 43 ©

Scope of Inspections The Product life-cycle 14 12 10 Marketing Authorisation GMP/GDP - PL/ML/WL

Scope of Inspections The Product life-cycle 14 12 10 Marketing Authorisation GMP/GDP - PL/ML/WL LICENCES Volume of 8 Product 6 4 GLP/GCP PHARMACOVIGILANCE Discovery 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time (Years) Gerald W Heddell – Managing the Risk – DIA China, May 2011 44 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment > Inspection MA CTA GLP GCP GMP GDP > Surveillance GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 45 ©

International Compliance International perspectives • Organisation for Economic Co-operation and Development (OECD) • Mutual

International Compliance International perspectives • Organisation for Economic Co-operation and Development (OECD) • Mutual Acceptance of Data (MAD) • OECD GLP Working Group Gerald W Heddell – Managing the Risk – DIA China, May 2011 46 ©

MUTUAL ACCEPTANCE OF DATA “Data generated in the listing of chemicals in an OECD

MUTUAL ACCEPTANCE OF DATA “Data generated in the listing of chemicals in an OECD member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice shall be accepted in other member countries for purposes of assessment and other uses related to the protection of man and the environment. 1981 Council Decision on Mutual Acceptance of Data (Annex 11) Gerald W Heddell – Managing the Risk – DIA China, May 2011 47 ©

Mutual Acceptance of Data 30 Member countries AUS, AU, BE, CAN, CZ, DK, FIN,

Mutual Acceptance of Data 30 Member countries AUS, AU, BE, CAN, CZ, DK, FIN, FR, GER, GR, HU, ICL, IRE, IT, JP, KO, LU, MEX, NL, NO, NZ, PO, PT, SK, SP, SWE, SWI, TU, UK, USA Argentina Brazil Malaysia (Provisional) Gerald W Heddell – Managing the Risk – DIA China, May 2011 Non-Member Economies • South Africa 2003 • Slovenia 2004 • Israel 2005 • Singapore 2010 • India 2011 Thailand China Russia etc. 48 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment MA CTA > Inspection > Surveillance GLP GCP GMP GPVP GDP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 49 ©

The Risk-based Model Intelligence Compliance Financial Company Regulatory Inspectorate Corporate compliance statement Company Questionnaire

The Risk-based Model Intelligence Compliance Financial Company Regulatory Inspectorate Corporate compliance statement Company Questionnaire Risk assessment process Inspection Output Inspection planning Inspection Organisational behaviour change Company Risk Assessor Inspectorate April 2008 Gerald W Heddell – Managing the Risk – DIA China, May 2011 50 ©

Risk-Based Inspection Model • Senior management from (the CEO down) must be demonstrably committed

Risk-Based Inspection Model • Senior management from (the CEO down) must be demonstrably committed - Taking responsibility for compliance - Leadership - Understanding - Provision of appropriate resources • Culture of process understanding and quality risk management • Robust and comprehensive change management • Robust investigations and acknowledgement Gerald W Heddell – Managing the Risk – DIA China, May 2011 51 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment CTA MA GLP > Inspection > Surveillance GCP GMP GDP GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 52 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 53 ©

Gerald W Heddell – Managing the Risk – DIA China, May 2011 53 ©

How we strengthen our system - UK Yellow Card Helping to make medicines safer

How we strengthen our system - UK Yellow Card Helping to make medicines safer Gerald W Heddell – Managing the Risk – DIA China, May 2011 54 ©

Trends in ADR Reporting 2004 -09 Gerald W Heddell – Managing the Risk –

Trends in ADR Reporting 2004 -09 Gerald W Heddell – Managing the Risk – DIA China, May 2011 55 ©

Best use of spontaneous Data? • Ability to detect risks not identified through trials

Best use of spontaneous Data? • Ability to detect risks not identified through trials • Observed over expected • Proactive pharmacovigilance – H 1 N 1 – HPV Gerald W Heddell – Managing the Risk – DIA China, May 2011 56 ©

Signals Signal detection Impact Analysis • Yellow Card data used for signal generation •

Signals Signal detection Impact Analysis • Yellow Card data used for signal generation • 242 signal case folders opened in year • 13 DSU articles based on YC data offering new advice to prescribers in 2009 RPPS Signal management review meeting Signal evaluation Regulatory action Gerald W Heddell – Managing the Risk – DIA China, May 2011 57 ©

Why is reporting ADRs important? Gerald W Heddell – Managing the Risk – DIA

Why is reporting ADRs important? Gerald W Heddell – Managing the Risk – DIA China, May 2011 58 ©

Because…. • they account for around 5% of hospital admissions • they cause death

Because…. • they account for around 5% of hospital admissions • they cause death in 1000 medical inpatients • they complicate drug therapy • they decrease compliance and delay cure Gerald W Heddell – Managing the Risk – DIA China, May 2011 59 ©

How common are ADRs? • Up to 40% patients in the community experience ADRs

How common are ADRs? • Up to 40% patients in the community experience ADRs • In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for 1 - 65, 000 emergency admissions/year - 12, 000 ulcer bleeding episodes/year - 2, 000 deaths/year 1 Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283 -291 Gerald W Heddell – Managing the Risk – DIA China, May 2011 60 ©

Why report ADRs? - 30 -50% are avoidable - Identifies new risks Gerald W

Why report ADRs? - 30 -50% are avoidable - Identifies new risks Gerald W Heddell – Managing the Risk – DIA China, May 2011 61 ©

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical

From Development to Patient – Managing the Risk Discovery and Development Pre-clinical Studies Clinical Trials Commercial Manufacture Distribution Managing Risk: - > Assessment MA CTA GLP > Inspection > Surveillance GCP GMP GDP GPVP - Adverse Drug Reaction Reporting - Medicines Testing Gerald W Heddell – Managing the Risk – DIA China, May 2011 62 ©

Medicines and Healthcare products Regulatory Agency Gerald W Heddell – Managing the Risk –

Medicines and Healthcare products Regulatory Agency Gerald W Heddell – Managing the Risk – DIA China, May 2011 63 ©

Medicines Testing Scheme • New Chemical Entities (NCE) • Inspectorate Samples • Enforcement Samples

Medicines Testing Scheme • New Chemical Entities (NCE) • Inspectorate Samples • Enforcement Samples • Licensing assessment samples • Defects • Unlicensed Medicines • Surveillance Programmes Gerald W Heddell – Managing the Risk – DIA China, May 2011 64 ©

Medicines Testing Samples Input PROTECTING Output PUBLIC Analytical Reports HEALTH Outcome Gerald W Heddell

Medicines Testing Samples Input PROTECTING Output PUBLIC Analytical Reports HEALTH Outcome Gerald W Heddell – Managing the Risk – DIA China, May 2011 Quality Improvements Regulatory Action Enforcement Action 65 ©

CONCLUSIONS • Patients expect medicines to be effective and safe • The assurance of

CONCLUSIONS • Patients expect medicines to be effective and safe • The assurance of safety and effectiveness is only as strong as the weakest link in the supply chain • Industry and regulators work together to provide assurance Gerald W Heddell – Managing the Risk – DIA China, May 2011 66 ©

Thank you for your attention Gerald W Heddell Director Inspection, Enforcement and Standards Division

Thank you for your attention Gerald W Heddell Director Inspection, Enforcement and Standards Division Medicines and Healthcare products Regulatory Agency +44 (0) 207 084 2500 gerald. heddell@mhra. gsi. gov. uk Gerald W Heddell – Managing the Risk – DIA China, May 2011 67 ©