Safeguarding public health

An Introduction to MHRA GCP Inspections

Michelle Rowson, GCP Inspector
GCP Compliance Unit Medicines and Healthcare products Regulatory Agency

March 2006

GCP Inspectorate
GCP Operational Manager Ian Oulsnam

Senior GCP Inspectors Gail Francis (H) Louise Mawer (H) Kath Williams (MT)

GCP Inspectors Andy Fisher (Y) Michelle Rowson (Y) Vincent Yeung (H) Kath Meely (MT) Jenny Black (Y) Rebecca Harrison (H) Pharmacovigilance Operations Manager Senior GCP Inspector
March 2006

Anya Sookoo (MT) Expert Inspector GCP and Pharmacovigilance

An Introduction to MHRA GCP Inspections Michelle Rowson

What do the GCP Inspectorate do?

Voluntary GCP Inspections (1997 2004): over 100 Statutory GCP Inspection Programme since May 2004

- Pharma, Clinical Labs - Non-commercial organisations - Niche Providers (ECG, Randomisation) - Contract Research Organisations
Triggered inspections based on reported cases of

suspected fraud or Regulator Assessor request

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Interactions with Europe

Regular European Medicines Agency (EMEA)

Inspectors Meetings
Networking and communication

Annual Training Event

Joint Inspections Development of SOPs and Guidelines

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Implementing the EU Directive in EU Member States

UK Statutory Instrument 2004:1031 introduced to implement EU Directive 2001/20/EC
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 1968 Section 112 (1))
Website link

http://www.opsi.gov.uk/si/si2004/20041031.htm

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Non-commercial Inspection How do we do it?

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

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Statutory Inspection Why you?

Periodic information from MHRA CTU and EudraCT, roll-over information from the CTX & DDX systems.

Preliminary information forms the basis of risk analysis

- Percentage of estimated total clinical trial population - Number of trials involving IMP

- Prior inspection history (both GCP and PV)

Ongoing identification of Contract Research Organisations and Sub-contractors

Non-commercial survey (louise.mawer@mhra.gsi.gov.uk)

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Pre-inspection Activities
Letter of notification sent out 2 -3 months in advance Pre-inspection dossier consists of:

- Company details: size/nature of activities,

organisation charts - Contact name to manage logistics

- List of trials dating back about a year

- SOP index & procedures in specific areas
Inspector reviews dossier & discusses inspection logistics Inspection dates and agenda agreed with organisation

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Activities of Interest
* Contract Management * Project management * Monitoring * Pharmacovigilance * Medical Advisors * Data management * Regulatory submissions * Quality Assurance * Training * Computer systems * Report writing * Archives

* Statistical Analysis

* Laboratories

* Investigational medicinal product management * Trial-file management for selected clinical trial(s) * Visits to selected investigational sites
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Example plan for Day 1

GCP INSPECTION PLAN {COMPANY NAME} INSPECTION REFERENCE NUMBER: {insert number}

DAY ONE: {date}

Opening Meeting Contracts & Agreements {initials} Project Management {initials} Lunch & Document Review Regulatory Affairs {initials}

Time
09.00 09.15 All Welcome

Personnel to be Interviewed

09.15 10.30 {insert names} 10.30 12.00 12.00 14.30 14.30 15.15

Trial Master File Review for the following 15.15 17. 30 studies: Round-up & Review for Following Day 17.30

{insert inspector initials identity} SOP copies should be made available in the office to be used by the inspection team. CVs, job descriptions and training records should be made available for the personnel interviewed and may be requested for other personnel. The times and activities listed above are provisional and may be adjusted during the inspection.
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

During Inspection (1)

Opening Meeting to confirm purpose of inspection, provide

introductions and methodology

Inspection conducted generally in accordance with the plan

may be revised based upon inspection outcomes

Combination of staff interviews, document review and

facility visits.
Use study specific examples to demonstrate the system Feedback of general findings at Closing Meeting
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

During Inspection (2)

General Expectations

Flexibility on both sides Open dialogue from the beginning Ongoing verbal feedback throughout the inspection Opportunity to demonstrate how your system meets the requirements of UK Statutory Instrument 2004:1031 - Review of action plans all ready in place to address known areas of non-compliance

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

What happens if things dont 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

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

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?

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

At the end of the trial:

Have the appropriate authorities been notified?

(including early termination)

Ethics Regulatory Authority Collaborator / sponsor

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Reports

Report issued within 30 working days of end of inspection Responses received within 30 calendar days of dispatch

Questions and clarification, if required

Summary letter and Inspection certificate produced

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

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
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Contract Management
Omissions, errors and discrepancies in contracts Responsibilities of collaborating parties not clearly defined Unclear ownership of documents and data Lack of consistency between protocol and contract Many activities delegated to Chief Investigator without

agreements or robust systems in place

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Quality Systems (1)
Lack of essential SOPs
Uncontrolled documents used in place of SOPs SOPs / Protocol do not reflect current practice or current

legislation
Insufficient time between SOP issues and becoming

effective, which leads to training issues

Meetings and decisions not documented In-process checks not documented

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Quality Systems (2)

- Internal audit programmes built around Research Governance Framework to meet Good Research Practice Guidelines
- These standards do not meet UK legislation requirements in relation to the Clinical Trials Directive - These standards do however form a sound basis on which to build compliant systems

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Investigational Medicinal Product
Missing or unsigned documentation:

- shipping records

- accountability
- dosing records
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 Ethical Approval

Lack of approval for study advertising

Study conduct at sites outside of those in the application

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP 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
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Pharmacovigilance Lack of involvement of Principal or Chief Investigator 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 Failure to monitor pregnancy to outcome Failure to monitor increased severity or frequency through trend analysis
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

UK MHRA GCP Inspection Findings

Miscellaneous Findings
Lack of documentation of validation of computer systems

Lack of GCP training or evidence of training

Study documentation not in secure place with restricted access Poor document control involvement of Principal Investigator variable

and not documented

Poor document control inadequate retention periods for

documentation
Unidentified or unexpected laboratory samples analysed

for a range of tests - this may be outside the protocol and therefore without consent
An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

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

Findings very similar to those in other

organisations - commercial/non-commercial alike

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006

Thank You for Your Attention

Any Questions?

An Introduction to MHRA GCP Inspections Michelle Rowson March 2006