Transcript PRODUCT QUALITY SURVEILLANCE IN THE MCA

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
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Crown copyright 2011
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Content
- Managing risk
- Lessons from history
- Regulatory processes
-
Assessment
Inspection
Surveillance
- Conclusions
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What is risk?
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The Meaning of Life - for the MHRA
MHRA Mission
The MHRA’s mission is to
enhance and safeguard the
health of the public by ensuring
that medicines and medical
devices work, and are
acceptably safe
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“If you do not manage
risk, it will manage you?”
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The History of Pharmaceuticals is a great success story
But also a catalogue of disasters!
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UK Therapeutic Substances Act (1925)
Reporting of Adverse Events
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US Federal Food, Drug and Cosmetic Act (1938)
Stricter controls on labelling, safety and listing
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Nuremburg Code (1947)
Protection of trial subjects
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UK Medicines Act 1968
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Phase 1 Accreditation for Clinical Trials
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METHOTREXATE, CHINA
• over 100 paralysed
• vincristine contamination
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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
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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
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HEPARIN, OBVIOUS LESSONS
• knowledge of supply chain
• risk assessment and management
• product specification
• involvement with suppliers
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Pedigree in EU GMP
QP declaration in EU MAs
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Heparin Supply Chain (Pedigree)
China
Pig Mucosa
China
+8 +1 SITE SITE SITE 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 SITE SITE 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
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SINGAPORE
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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
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Supply Chain Pedigree
-
GMP Guideline requirements
-
QP Declaration in MA dossier
Also required by
US Drug Safety and Accountability Act 2010
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Is it possible to overt risk before disaster happens?
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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
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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
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Clinical Trials
– Approval and Good Clinical Practice
Legal Framework: Directive 2001/20/EC
transposed into national law
Guidance Documents:
ICH
European Commission
EMA
National
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Assessment of CT applications: National
Member State responsibility, not at a
European Lead
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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)
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GCP Directive
2005/28/EC of 8th April 2005
-
outlines GCP principles
GMP Directive
2003/94/EC of 8th October 2003
-
GMP principles
-
Inspections
-
Quality Management Systems
-
Labelling
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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
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National Competent Authority (NCA)
Timescales
TOTAL TIME = 60 DAYS
AUTHOR.
EudraCT
Number
No
No
GNA
GNA
Yes
RESP
APP
Yes
REJECT
30D
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14D
16D
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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
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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
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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
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The CTD
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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.
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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)
DeCentralised Procedure (DCP)
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Overview of Procedures (1)
National Procedure
 UK only
 Follow internal targets for assessment
 Less popular now
 National variations
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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
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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)
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Overview of Procedures (4)
DeCentralised 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
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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
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Scope of Inspections
The Product life-cycle
14
12
10
Marketing
Authorisation
Volume
of
8
Product
6
4
GMP/GDP - PL/ML/WL LICENCES
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)
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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
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International Compliance
International perspectives
• Organisation for Economic Co-operation and
Development (OECD)
• Mutual Acceptance of Data (MAD)
• OECD GLP Working Group
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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)
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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
Non-Member Economies
• South Africa 2003
• Slovenia 2004
• Israel 2005
• Singapore 2010
• India 2011
Argentina
Brazil
Malaysia
(Provisional)
Gerald W Heddell – Managing the Risk – DIA China, May 2011
Thailand
China
Russia
etc.
48 ©
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
Risk
assessment
process
Inspection
Output
Inspection
planning
Inspection
Organisational
behaviour
change
Company
Risk Assessor
Inspectorate
April 2008
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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
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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
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Gerald W Heddell – Managing the Risk – DIA China, May 2011
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How we strengthen our system - UK
Yellow Card
Helping to make medicines safer
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Trends in ADR Reporting 2004-09
Spontanous ADR reporting by source 2004-2009
30000
80000
70000
25000
Patient
60000
No. reports/year
50000
15000
40000
30000
10000
20000
Cumulative reports
HCP
20000
Industry
Patient
cumulative
HCP
cumulative
Industry
cumulative
5000
10000
0
0
2004
2005
2006
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2007
2008
2009
Note: Patient reporting
was introduced in Jan
2005
55 ©
Best use of spontaneous Data?
• Ability to detect risks not identified through trials
• Observed over expected
• Proactive pharmacovigilance
– H1N1
– HPV
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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
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57 ©
Why is reporting ADRs important?
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Because….
• they account for around 5% of hospital
admissions
• they cause death in 1 in 1000 medical inpatients
• they complicate drug therapy
• they decrease compliance and delay cure
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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 for1
- 65,000 emergency admissions/year
- 12,000 ulcer bleeding episodes/year
- 2,000 deaths/year
1Blower
et al. Emergency admissions for upper gastrointestinal disease
and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283291
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Why report ADRs?
- 30-50% are avoidable
- Identifies new risks
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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
62 ©
Medicines and Healthcare products
Regulatory Agency
Gerald W Heddell – Managing the Risk – DIA China, May 2011
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Medicines Testing Scheme
• New Chemical Entities (NCE)
• Inspectorate Samples
• Enforcement Samples
• Licensing assessment samples
• Defects
• Unlicensed Medicines
• Surveillance Programmes
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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 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
Medicines and Healthcare products Regulatory Agency
+44 (0) 207 084 2500
[email protected]
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