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

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

Group Manager Inspections 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

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

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

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

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 So what is likely to happen during the visit? We would expect at least 2 GCP inspectors to be on site. They may wish to see a tour of some of the facilities e.g. the CRF, pharmacy, laboratories etc. They may ask to see additional documentation not submitted as part of the Pre-Inspection Dossier – for example other policies or SOPs . As you can imagine, we had to be selective as to what we included in one lever arch file. They will want to inspect several clinical trials to test systems. These could be studies which are ongoing or studies that have closed since May 2005. If they decide they are particularly interested in close down or archiving systems they may well choose a study that has closed. Who will they wish to interview? Well of course we can’t be certain but from past experience, for the chosen trials they will usually interview the Chief/Principal Investigator and other key members of the same research team. They usually interview these individuals separately. We expect they will interview key individuals in the R&D Office and probably key individuals in Pharmacy, the laboratories, medical records, IT, radiology. As this is a statutory inspection, individuals are expected to make themselves available. As there is usually 4-6 weeks notice, clinicians would be expected to make alternative arrangements for clinics, ward rounds etc. The R&D office will of course do everything it can to try and schedule the timetable of interviews to suit both the MHRA AND staff here at the Trust. Once we know which studies are to be inspected in detail, we will ask for a named contact in the trial team to liaise with the R&D office over the logistics of the Inspection as we will be expected to provide suitable rooms for interview, access to office space and access to photocopiers etc. A member of the R&D Office will attend each interview as notes must be taken.

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.

Response to Findings Organisation must respond within 30 days Critical Findings or a number of Major Findings may lead to suspension of one or all CTIMPs in the organisation Organisation response Analysis of findings Corrective Action Preventative Action Plans of assessing effectiveness of preventative action Timelines Disputed findings

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

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)

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

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

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

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

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

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

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