1. © Safeguarding public health Lynne Byers An Introduction to MHRA and GCP Inspections – Lynne Byers Medicines and Healthcare products Regulatory Agency March 2006

2. Lynne Byers An Introduction to MHRA and GCP Inspections © Agenda GCP Inspectorate Activities GCP Framework for Inspection Selection (Routine Systems Inspections) The Non-commercial Survey The Inspection Process Common MHRA GCP Findings

3. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © What does the GCP Inspectorate do? Interactions with Europe Interactions with stakeholders (internal and external) -Interface with MHRA assessors, CTU, PV Unit, Enforcement etc. -Training of other inspectors -Consultative Committee, presentations, symposia, queries -Review of legislation and guidance documents Statutory GCP Inspection Programme since May 2004 -Pharmaceutical organisations, Clinical Laboratories -Non-commercial organisations -Niche Providers (ECG, Randomisation) -Contract Research Organisations

4. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © The EU Directive in the UK Statutory Instrument 2004:1031 implementing Directive 2001/20/EC: The Medicines for Human Use (Clinical Trials) Regulations 2004 Website link http://www.opsi.gov.uk/si/si2004/20041031.htm Power to inspect (GCP, Laboratories, GMP) any site involved in a clinical trial in the UK (Schedule 9, Regulation 47(1) point 7 via amendment of the Medicines Act) Amendment due for implementation of Directive 2005/28/EC (Detailed guidelines for Good Clinical Practice) For non-commercials: specific modalities

5. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Statutory Inspection – Why you? Routine or Triggered Inspection Routine inspection based upon risk assessment process Survey underway to gather information in relation to GCP risk factors Triggered inspections in response to queries, referrals etc. Background to the Survey Current scheduling arrangements: 5 - 10% of Statutory Inspections Is this representative of the clinical trial patient population or research workload? Which non-commercial organisations have been inspected to date? Charities, NHS Hospital Trusts, one University Results? Some quality system & PV issues How representative are these results?

6. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © The Process Baseline questionnaireRisk Factors Number & nature of clinical trials Number of investigators (on/off site) Approximate number of trial subjects IMP PV Quality systems Establish database & analyse data Identify organisations for inclusion in the schedule Roll-out MHRA Non-commercial Survey

7. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Next Steps Data Analysis & Follow-up Identify ‘key players’ & organisations potentially of high risk Follow-up sample of questionnaires & non-responders Draft schedule to run in parallel, & complimentary to current schedule Time-lines First questionnaires distributed December 2005 Queries coming in First questionnaire deadline mid February 2006 Database & follow-up by end March 2006 Full schedule roll-out financial Q2 onwards

8. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Non-commercial Inspections How do we do them? Same regulatory framework & reference standards Same inspection documentation Same inspection objectives Different scope to interview sessions – recognise one person wears ‘many hats’ Different funding & sponsor arrangements Different trial approval processes Potential to combine sponsor/investigator inspections

9. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © What will happen? (Routine Systems) Annual Plan produced; rolling programme of notification Advance notification - two to three months Pre-inspection dossier - ONE lever-arch file Contact name to manage the logistics Company details: size & nature of activities, organisation charts List of trials (under the Directive) dating back about a year SOP index & procedures in specific areas Inspector reviews dossier, contacts organisation with proposed dates, works with organisation on the plan

10. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Activities of Interest * Contract Management * Regulatory submissions * Project management * Quality Assurance * Monitoring * Training * Pharmacovigilance * Computer systems * Medical Advisors * Report writing * Data management * Archives * Statistical Analysis * Laboratories * Investigational medicinal product management * Trial-file management for selected clinical trial(s) * Visits to selected investigators/investigator sites

11. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © During Inspection Opening Meeting: introductions, confirm purpose of inspection, discuss expectations, plan & methodology Inspection is a combination of staff interviews, document review and facility visits; generally conducted in accordance with the plan – BUT plan may be revised based upon inspection outcomes Study specific examples used to demonstrate the system Feedback of general findings at Closing Meeting Written report within 30 days of the last site inspection - opportunity for the organisation to respond to findings Follow-up (where necessary) to close-out

12. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © General Expectations Flexibility on both sides Open dialogue from the beginning Ongoing verbal feedback throughout the inspection Review of action plans all ready in place to address known areas of non-compliance Opportunity to demonstrate how your system meets the requirements of UK Statutory Instrument 2004:1031

13. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © What happens if things don’t go to plan? ‘Back to Basics’ Model for Inspection: Before the Trial starts - Are the appropriate approvals in place? Trust/Management Approval (sponsor & indemnity arrangements) Ethics Approval Regulatory Approval

14. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Back to Basics Inspection (continued) During the Clinical Trial Is the trial being conducted in accordance with the principles of GCP? Is there a controlled process for writing, review and approval of protocol amendments? Is there an adequate Pharmacovigilance system in place? Are there adequate records for historical reconstruction purposes At the end of the trial Have the appropriate people been notified? (including early termination) Ethics, Regulatory Authority, Trust, collaborator / sponsor...

15. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © MHRA Clinical Trials Inspection Action Group (CTIAG) Referral for inspections with critical findings Management level, multi-disciplinary group to advise MHRA Directors on potential referrals Primary objective: protection of public health by ensuring that clinical trials of investigative medicinal products meet the required regulatory standards What does this mean? For the Inspector:rapid communication of critical issues For the Inspectee:urgent corrective action to ensure compliance

16. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © MHRA GCP Inspection Findings Contract Management Omissions, errors and discrepancies in contracts Responsibilities of collaborating parties not clearly defined Many activities delegated to Chief Investigator without agreements or robust systems in place Informed Consent No records of consent being taken Inconsistencies with protocol/amendments Poor version control/incorrect form used Unclear process

17. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © MHRA GCP Inspection Findings Quality Systems Internal audit programmes built around Research Governance Framework to meet ‘Good Research Practice Guidelines’ These standards form a sound basis on which to build systems, but alone do not meet UK legislative requirements in relation to the Clinical Trials Directive Lack of approved, controlled, documented procedures (SOPs) Uncontrolled documents used in place of SOPs SOPs / Protocol do not reflect current practice or current legislation Failure to keep pertinent and complete records: e.g. key meetings/decisions not documented, in-process checks not documented, inability to reconstruct the trial from the records

18. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Miscellaneous Findings Lack of GCP training or evidence of training Computerised systems not validated Study documentation storage insecure or inadequate retention periods Unidentified or unexpected laboratory samples analysed for a range of tests - this may be outside the protocol and therefore without consent Investigational Medicinal Product Missing or unsigned documentation - accountability, dosing, shipping Emergency codes not supplied concurrent with supplies, or prior to study start Insufficient records for the chain of custody (from purchase to destruction) for marketed products used in clinical trials MHRA GCP Inspection Findings

19. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © MHRA GCP Inspection Findings Pharmacovigilance Lack of awareness of legislative requirements (7 and 15 day reports) Failure to distinguish AEs and ADRs Failure to identify ‘Serious events’ Failure to consider event expectedness, and hence to identify events which require IMMEDIATE reporting Lack of involvement of Principal or Chief Investigator Failure to monitor pregnancy to outcome Failure to monitor increased severity or frequency through trend analysis

20. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © MHRA Experience of Non-commercial Organisations Very open to recommendations & proactive in response to inspection findings Willing to develop systems through extensive networks Findings often in-line with those identified by internal audit/R&D function Many findings very similar to those in other organisations - commercial/non-commercial alike

21. March 2006 Lynne Byers An Introduction to MHRA and GCP Inspections © Thank You for Your Attention Any Questions?