Transcript MHRA powerpoint template - National Patient Safety Agency

Safeguarding public health
Summary of Inspection
Findings 2006 - 2007
Information Exchange under Memorandum of Understanding
Louise MAWER
April 2007
©
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Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Content
• GCP Inspectorate Organisation (resource)
• Routine Inspection Model
• Types of Inspection
• Inspection Format & Reporting
• Number & Nature of Inspections (2006 – 2007)
• Number, Nature & Source of Critical Findings
• Summary
• Example Findings (Appended for Information)
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
GCP Inspectorate Organisation
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
INSPECTION AND STANDARDS DIVISION
Group Manager, Inspections
(GLP/GCP/PV)
Ms Rebecca Harrison
Operations Manager
GCP
(Appointment Pending)
Operations Manager
PV
Welwyn Garden City (WGC)
Tel: 01707 299130
Michael Bean
Team Members
Team Members
Senior Inspectors
Gail Francis
Louise Mawer
Kathleen Williams
(WGC)
(WGC)
(MT)
Inspectors
Jennifer Black
Andy Fisher
Kathleen Meely
Mark Poulton
Michelle Rowson
Vincent Yeung
Jason Wakelin-Smith
(Y)
(Y)
(MT)
(WGC)
(Y)
(WGC)
(WGC)
Senior Inspector
Lindsay Watt
(WGC)
Inspectors
Andrew Cochrane (WGC)
Jo Harper
(WGC)
Calvin Johnson (MT)
Patricia Moore
(MT)
Johanna Piper
(MT)
Kevin Perkins
(WGC)
Carrie Scott
(MT)
Manjit Virdee
(WGC)
Keith Wibley
(MT)
Operations Manager
GLP
Market Towers (MT)
Tel: 0207 084 3510
Andrew Gray
Team Members
Expert Inspector
Steve Monk
(WGC)
Senior Inspector
Lesley Graham (WGC)
Inspectors
Samantha Atkinson (Y)
Mary Baynes
(WGC)
Expert Inspectors
GCP/PV
Anya Sookoo
Ian Oulsnam
(MT)
(MT)
GXP matters only
Steve Monk
(WGC)
Administrators
Eugenie James
Joanna Milborrow
Janet Lander
Joyce Rhodes
Janet Symes
(MT)
(WGC)
(WGC)
(York, (Y))
(Y)
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Routine Inspection Model
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Routine Inspection Model
Re-inspection
Plan
Close
Conduct
Response
Review
Report
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Routine Statutory GCP Inspections
Inspection Conduct
• Combination of staff interviews, facility visits and
documentation review
• Commercial model: sponsor + investigator site visits
• Non-commercial model: combined visit, may include several
sites
• Key activities, key staff – all directed to clinical trial function of
the concerned organisation
• Key records reviewed to reconstruct the trial – includes the
ethics opinion which includes the documents receiving a
favourable opinion, and the list of sites notified to the main
ethics committee
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Types of GCP Inspections
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Other GCP Inspections
• Routine Systems – covers all clinical trial activities
• Routine Study-specific Inspection
- Detailed review of a study; data-directed
• Triggered
- Conducted in response to an issue, ‘for cause’ and
directed towards a specific question
- Referral from internal or external source for example
ethics committee, concerned member of public etc
• Requested
- Conducted to support license application/extension
- UK, Europe or other regulatory request
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Inspection Format & Reporting
• Opening meeting, conduct, closing meeting
• Findings categorised: critical, major, other
• Verbal preliminary feedback of outcome, typically at the
closing meeting
• Inspection report: written findings 30 working days after the
last site inspection
• Inspection report responses received and reviewed
• One opportunity for revision/addition to responses if
responses incomplete/unsatisfactory
• Inspection closed and statement of inspection issued
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Nature of Inspections
(2006 – 2007)
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Nature of Inspections
Type of Organisation
Pharmaceutical Company (routine systems)
Number
Inspected
38
Hospital Trust (routine systems)
10
Contract Research Organisation (routine systems)
12
Phase I Unit (routine systems)
14
Study-specific Inspection
3
Laboratory
1
Other non-commercial (for example charitable organisation)
2
Other commercial (for example niche service)
2
Triggered
5
All figures calculated from inspection reports available from inspections performed to 31-Mar-07; total 87
(>90% inspections conducted (total completed 96))
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number, Nature & Source of Findings of
Significance
(Major & Critical Findings 2006 – 2007)
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Source of Critical Findings
Source of Findings
Routine Systems: Pharmaceutical Company*
Routine Systems: Non-commercial Organisations
Routine Systems: Contract Research Organisations
Routine Systems: Phase I Units
Study-specific Inspections
Triggered
Total
Number of
Inspections with
Critical Findings
1
8
4
3
2
4
22
(25%)
* A number of findings in other routine system inspections were attributable to pharmaceutical sponsor
responsibilities
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Source of Critical Findings
Nature of Critical Findings
Number of
Findings
Confidentiality/Subject’s Rights
IMP Management
Sponsorship & Authorisation Issues
GCP & Study-specific/Protocol Compliance
Data Management & Statistics
Contracts, Agreements & Insurance
Informed Consent
Periodic Updates including Required Notifications
Pharmacovigilance & Safety Monitoring
9
5
4
3
3
1
1
1
1
Control Systems/Project Management
1
IMP Qualified Person Eligibility
1
30
Total
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Source of Major Findings
Nature of Major Findings
Number of
Findings
Confidentiality/Subject’s Rights
IMP Management (12%)
Sponsorship & Authorisation Issues
GCP & Study-specific/Protocol Compliance
Data Management & Statistics (4%)
Contracts, Agreements & Insurance (14%)
Informed Consent
Periodic Updates including Required Notifications
Pharmacovigilance & Safety Monitoring (11%)
2
36
8
7
13
41
6
2
33
Control Systems/Project Management (7%)
21
Multiple Quality System Issues (8%)
24
Sub-Total
193
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
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Number & Source of Major Findings
Nature of Major Findings
Number of
Findings
Standard Operating Procedures, Policies & Other Procedures (8%)
Out of Hours Cover & Medical Advice (6%)
Archives (5%)
Quality Assurance & Quality Control (4%)
Training
Computerised System Validation
Recruitment Issues
Document Control & Trial Filing
Monitoring
Medical Writing/Reports
Facilities
Lab Systems & Equipment
23
18
15
12
6
6
6
5
3
3
2
2
Sub-total
101
Total
294
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Summary
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Summary
• Only 2% of inspections had no major or no critical findings
• 21* Organisations have been referred to the GCP Inspection Action
•
•
•
•
•
•
•
Group for critical findings in 2006 – 2007 (*Mar-07 referrals pending at summary)
67% Non-commercial routine systems inspections had critical findings
compared to 14% Commercial routine systems inspections
21% Phase I Units had critical findings
60% Triggered inspections (all sectors) had critical findings
A number of findings in differing sectors have critical findings related to
the sponsor responsibility but these have not been quantified
67% Study-specific (Pharma) inspections had critical findings
69% (60/87) Inspections had multiple and serious major findings
(multiple major findings classed as 3 or more)
Multiple major findings break-down by sector: Pharma 66% (25/38),
CROs 67% (8/12), Phase I 93% (13/14), Non-commercial 75% (9/12),
Triggered 40% (2/5)
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Summary
• 30% of critical findings related to confidentiality and subject’s rights
• Contractual agreement & insurance findings are most common
• Almost all non-commercial inspections have resulted in major or critical
findings for pharmacovigilance (PV)
• A significant number of commercial organisations have also had findings
in PV
• Quality system and IMP-related findings are common
• For non-commercial organisations sponsorship and authorisation issues
are common
• Almost all errors detected could have been identified through robust
quality control and quality assurance procedures directed to the national
& European regulatory framework
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Inspection Findings
Contracts, Agreements & Insurance
• Missing/draft/unsigned contracts, responsibilities not clearly defined, unclear
ownership of documents and data, lack of consistency in detail, failure to agree
regulatory responsibilities
• Insurance policy terms and conditions with exemptions; for example certain
patient populations, in absence of compliance with protocol etc – very common
that these terms & conditions are NOT reviewed by the organisation purchasing
the cover or to whom cover is extended
Investigational Medicinal Product (IMP)
• Missing documentation – no records/partial records to confirm who got what,
when
• Supplies which do not have documentation to confirm UK/European
requirements for quality and compliance with the trial authorisation(s) – failing or
missing ‘green light’ process bringing management approval
(insurance/indemnity), ethical and regulatory approval together
• Emergency codes not supplied concurrent with the trial medication or prior to
the study start
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Inspection Findings
Informed Consent
• No records of consent being taken, missing elements, inconsistencies with
protocol, forms not updated with amendments, poor version control, incorrect
form used, unclear process
• Record of consent with patient identifying details sent to central data centre
Subject Safety and Confidentiality
• Pharmacovigilance findings – Adverse Events (AEs), Serious Adverse Events
(SAEs), Suspected Unexpected Serious Adverse Reactions (SUSARs);
inconsistencies in records
• Lack of evidence of involvement of key researcher (e.g. investigator, Principal
Investigator, Chief Investigator)
• No confirmation of identity of volunteers (Phase I)
• Unclear out of hours emergency procedures / failure to test the procedure,
subjects not supplied with emergency contact details
• Subject details sent outside of the investigator institution, e.g. to the Sponsor or
another trial unit/hospital particularly noted on hospital lab reports with SAEs
• Ineligible subjects entered into the studies
• Waivers used inappropriately & regularly
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Inspection Findings
Quality & Control Systems
• Multiple issues e.g. no/poorly documented training, no audit or monitoring
process, document control and document management issues
• Key procedures not documented or not reflective of current practice/legislation,
uncontrolled documents used for key processes such as adverse event
collection, protocols & amendments
• Failure to implement in-process checking procedures (quality control)
• Failure to maintain an over-sight of contractors/diverse decentralised functions
Ethical Approval
• Lack of approval for study advertising – especially websites
• Study conduct at sites outside of those in the application
• Failure to notify sites for site-specific assessment exemption
• Use of documents which are not those which received a favourable opinion or
untimely re-consent where documents are revised
• Ambiguity in what did receive a favourable opinion for example through
typographical errors/omissions in the correspondence
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©
Inspection Findings
Resource & Facility Issues
• No cover for system in absence of responsible person – for example system
stops for annual leave/sickness
• Housekeeping and archiving issues - particularly failure to control records in
appropriate environment for full retention period
Miscellaneous Findings
• Failure to send updates/annual reports and amendments
• Lack of documentation of validation/fitness-for-purpose assessment of
computerised systems used for key clinical trial activities
• Data integrity and database issues including uncontrolled unlock/re-lock;
inconsistency in source and database records
• Equipment related findings and failure to maintain appropriate documentation
• Unidentified or unexpected laboratory samples analysed for a range of tests this may be outside of the protocol and therefore without consent
Summary of Inspection Findings 2006 - 2007
Louise MAWER
April 2007
©