The inspectors Inspection process Inspection Outcomes Preparing for the Inspection

1. Medicines and Healthcare products Regulatory Agency (MHRA) Statutory Good Clinical Practice (GCP) Inspection of Cardiff University

2. The plan for today • The inspectors • Inspection process • Inspection Outcomes • Preparing for the Inspection • Experience of an inspection

3. The Inspectors GCP Inspectors Offices: York Welwyn Garden City Market Towers GMP Inspectors Group Manager Inspections GLP Inspectors GPvP Inspectors Expert Inspectors Serious Breach of GCP

4. What does an inspection involve? http://www.mhra.gov.uk/CON2024532

5. Pre-Inspection Dossier • Complete list of Clinical Trials (from May 2005) • Organisational charts • Overview of all facilities • Description of archiving arrangements • SOP index • Detailed procedures in relation to: • Trial management • Quality control and assurance • Computerised systems • Equipment maintenance • Supply of Investigation Medicinal Product • Laboratory procedures • Activities carried out by CU or contracted out by CU

6. Clinical Trial Activities Any activity involved in the running of Clinical trials at our institution Archiving SOPs Statistics Adverse Event reporting Contracts Data Management Drug Management Trial reporting Project Management Training Laboratory Randomisation Computer Systems Regulatory approvals Study Monitoring Trial Files

7. What happens during the visit? • 1 week inspection by at least 2 GCP Inspectors • Documentation review • University/School/Unit SOPs • Facility Visits • Inspection of several clinical trials to test systems • Interviews with key personnel, e.g. • Chief / Principal Investigator • Research teams e.g. Research Fellow, Research Nurse • RACD • Laboratories • IT • Archiving facilities • Inspection plan can change

8. Inspection outcomes 3 categories of findings: Critical: • evidence that i) the safety, well-being or confidentiality of trial subjects have been or have potential to be jeopardised, ii) the clinical trial data are unreliable iii) there are a number of Major non-compliances, indicating a systematic quality assurance failure. • insufficient or untimely corrective action regarding previously reported Major non-compliances Major: • significant and unjustified departure from legislative requirements that may develop into a critical issue unless addressed, • a number of departures from legislative requirements and/or established GCP guidelines, indicating a systematic quality assurance failure. Other: • departure from legislative requirements and/or established GCP guidelines, but it is neither Critical nor Major.

9. Common Findings • Contract & Agreement Preparation • Lack of written agreements with collaborators • Inconsistencies between protocol and contract • Delegation of duties without agreements/systems in place • Lack of identification of CI and all trial team at outset • Quality System • Lack of SOPs • Insufficient time between issuing and implementing SOPs, leading to training issues • Team meetings not documented • Training • Inadequate knowledge of Clinical Trial Regulations • Lack of GCP training amongst trial team • Informed Consent • No record of consent • Incorrect version

10. Common Findings • Investigational Medicinal Product (IMP) management • Inadequate provisions for storage of IMPs • Insufficient records for the chain of custody • Inadequate procedures for QP release • Lack of documentation confirming role of Pharmacy/CI • Pharmacovigilance • Inadequate Pharmacovigilance systems and/or inadequate use of systems in place • Lack of awareness of legislative requirements • Standardisation or arrangements for un-blinding SAEs arising from blinded trials • Annual safety report to MHRA not made • Data management • Security of trial documents/data • Inadequate retention period • Lack of clarity of data entry and data query processes (Source Data Verification)

11. Common Findings • Information Management • Lack of assurance that systems are fit for purpose • Lack of evidence of system security • No clarity on arrangements for backing up data • Regulatory Affairs (e. g. Clinical Trial Authorisations) • Remarks on MHRA approval letters not followed up • Unclear indemnity arrangements • Unclear sponsorship arrangements for DDX studies • Annual and end of study reports not sent • Filing of essential documents • Poorly maintained site files • Poor document control and management • Forms not signed or not completed correctly • Laboratory • No evidence of how equipment is maintained, calibrated and serviced

12. University (RACD) Preparations • Pre-Inspection Dossier • Awareness Raising • Delegation of duties • Review of Clinical Trial list • Clinical Trial Monitoring Visits - essential documentation • MHRA Inspection working group • Risk Assessment/GAP analysis – based on common findings from previous MHRA inspections • Individualised preparation plans

13. How can Research Groups/Units prepare? • Awareness raising • Familiarity with legislation, internal and external guidance • ICH GCP (Topic E6) http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf • University Research Governance web page http://www.cf.ac.uk/racdv/resgov/index.html • www.ct-toolkit.ac.uk • GAP analysis • Essential documentation / Unit SOPs • Action plan

14. How can Researchers prepare? • Familiarity with legislation, internal and external guidance • ICH GCP (Topic E6) http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf • University Research Governance web page http://www.cf.ac.uk/racdv/resgov/index.html • www.ct-toolkit.ac.uk • Essential Documentation - Self-assessment of the trial using Trial Master File checklist • Approvals • Document Control • IMP management • Delegation Logs • SOPs • Pharmacovigilance • Equipment

15. Summary • Anyone involved in Clinical Trials • Co-operation and engagement • Early Preparation • Action plan to remedy issues

16. Contacts Research Governance Team resgov@cardiff.ac.uk X79277 (01798 79277 from Heath) Chris Shaw Matthew Harris Kathy Pittard Davies

17. Medicines and Healthcare products Regulatory Agency (MHRA) Statutory Good Clinical Practice (GCP) Inspection of Cardiff University