Good Clinical Practice

Introduction
The MHRA Good Clinical Practice (GCP) Inspectorate is part of the Inspections & Standards Division of the MHRA. It assesses the compliance of organisations conducting clinical trials using investigational medicinal products with UK and EU legislation.

It is one of the five medicines inspectorates at the MHRA. The other four being:

In this section you will find information regarding the working of the GCP Inspectorate, its responsibilities and powers as well as details of its work.  We have presented the information in an easy to follow question and answer format but if you require any further information please do not hesitate to contact us.

What is Good Clinical Practice (GCP)?
Definition from EU Directive 2001/20/EC, article 1, clause 2:
“Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects.”

Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible and accurate.

The principles of good clinical practice are outlined in articles 2 to 5 in the EU Directive 2005/28/EC.

ICH Topic E 6, the ICH Note for Guidance on Good Clinical Practice is an international standard for GCP. It was adopted by the CPMP (CPMP/ICH/135/95) I July 1996 and became operational in the European Union (EU) in January 1997. The ICH Note for Guidance on GCP replaced the previous European Community GCP Guidelines, which were implemented in 1991.

What is the MHRA GCP Inspectorate?
In the UK, the GCP inspectorate is responsible for inspecting clinical trials for compliance with Good Clinical Practice.  Statutory Instrument 2004/1031 and subsequent amendment 2006/1928 provides the legal basis for these inspections (see links below).

Inspections relating to the manufacture of Investigational Medicinal Products (medicines being tested) are carried out by GMP inspectors.

This statutory instrument implements, in the UK, the EU Directive 2001/20/EC, "on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use” and the EU Directive 2005/28/EC, “laying down the principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products.”

The GCP inspectorate consists of a team of GCP inspectors.  By conducting inspections at the sites of organisations conducting or involved in clinical trials, the GCP Inspectors assess compliance with the requirements of legislation and guidelines relating to conduct of clinical trials involving investigational medicinal product. Each Inspector has a statutory duty to assess compliance with medicines legislation and holds a warrant accordingly.

What does the MHRA GCP Inspectorate do?
The function of the GCP Inspectorate is to assess the compliance of organisations with UK and EU legislation relating to the conduct of clinical trials in investigational medicinal products. This is achieved through carrying out inspections of sponsor organisations that hold clinical trial authorisations (CTA) or organisations that provide services to clinical trial sponsors.  These include pharmaceutical companies, contract research organisations, non-commercial organisations such as universities, NHS Trusts and charities, investigational trial sites, clinical laboratories, GCP archives and other facilities involved in clinical trial research. GCP inspections may also take place following a referral, i.e., information received by the inspectorate relating to GCP non-compliance.

MHRA GCP inspectors attend the ad hoc meetings of EU GCP Inspectors, which are held on a quarterly basis at the EMEA. The aim of these meetings is to assist with harmonisation and the development of procedures, for EU GCP inspections.  The inspectorate also provides UK representation at the Commission for the development of GCP legislation and guidance.

The MHRA GCP Inspectorate has participated in joint GCP inspections with inspectors from a number of EU Member States. In addition, the GCP Inspectorate has been instrumental in providing advice and training to GCP inspectors from countries within and outside the EU. GCP Inspectors participate in clinical research seminars and training courses.

GCP Inspectors also shadow inspections conducted in the UK, by foreign agencies, for example, the American FDA, the Japanese Ministry of Health and Welfare.

The GCP inspectorate organises  a GCP consultative committee with relevant interested parties and also answers any queries, for example relating to GCP issues, GCP inspections and also, parliamentary questions.  The GCP Inspectorate holds symposia every year, in which updates from the inspection programme and new issues that may impact on the conduct of research e.g. new legal requirements, are reviewed.  For upcoming events provided by the MHRA please visit the Conferences Section. 

The inspection process

Types of inspection
There are three types of GCP Inspections:

  • Routine inspections: inspections of the systems and procedures used to conduct clinical research in the UK by both commercial and non-commercial organisations, in order to assure compliance with applicable legislation.  Organisations are notified of routine inspections in advance.
  • Triggered inspections: these are ad hoc inspections that may be triggered as a result of MHRA licensing requests or reports received by the MHRA on suspected violations of legislation relating to the conduct of clinical trials. In rare circumstances the organisation may not be notified of these inspections in advance.
  • CHMP requested inspections resulting from central MA submissions: the CHMP can request GCP inspections in relation to marketing applications made using the EU centralised procedure. The EMEA (The European Medicines Agency) co-ordinates these inspections, which are conducted by inspectors from the EU Member States. The MHRA GCP Inspectorate participated in the first EMEA co-ordinated EU GCP inspection and, on request, continues to participate in EU GCP inspections (which are conducted both within and outside the EU)

Routine inspection process flowchart
A flowchart of the routine inspection process can be viewed using the link below.
› GCP routine inspection process (365Kb)

Submission of the requested information for routine inspections
Preliminary notification is sent out to those organisations identified for inspection. This request for information includes a list of clinical trials, organisation charts, SOP lists and selected SOPs, key contact details, overview of facilities, key service providers and clinical trials activities. This should be a summary that can fit into one lever-arch file. The organisation supplies the dossier as requested by letter. The dossier is the basis on which the inspectors allocate resource, develop the inspection plan and set the provisional organisation fee category.  The inspection plan is developed with the organisation to ensure all activities are covered and appropriate personnel are available for interview.  A number of clinical trials are normally selected for detailed Trial Master File (TMF) review, although the inspection may NOT be limited to these.

› GCP inspection dossier (42Kb)
› GCP inspection dossier checklist (74Kb)
› Clinical trial spreadsheet for GCP inspection dossier (9Kb)

What to expect during a routine inspection
The inspections consist of site visits to the organisation and, where appropriate, selected clinical investigator sites.  The inspection will start with an opening meeting where the Lead Inspector will outline the scope and purpose of the inspection, confirm the inspection plan and introduce the inspector(s). During the inspection the inspectors will request additional documentation and the organisation should be prepared to provide this promptly during the inspection.  Interviews with relevant personnel, generally as per the inspection plan are conducted.  Time is built into the inspection for the review of documentation, for example the TMF for the selected clinical trials. The inspector may visit any facilities involved in clinical trials, for example data management units, archives, pharmacy and these visits may be pre-arranged by the inspector for logistical reasons or decided upon during the inspection.  During the inspection, the inspectors reserve the right to change the inspection plan, for example additional interviews or time may be required dependent upon inspection findings.  At the end of the inspection there will be a closing meeting where the findings are reported verbally to the organisation, the next steps given regarding any further sites to be inspected and the timescales for the report.

Findings and reporting of routine inspections
The grading of deficiencies found during inspection or subsequent to post-inspection review are classified as “Critical”, “Major” and “Other” findings (see definitions below). In addition the inspectors will make some observations and recommendations in the report.
› GCP inspection findings classification (11Kb)

Once the inspection has been completed an Inspection Report is prepared by the lead inspector after the last site visit or on receipt of the last document requested, which ever is later. It should be noted that the factual matter contained in the Inspection Report relates only to those things that the inspection team sees and hears during the inspection process. Once adequate responses have been received from the organisation, a closing letter and GCP Inspection Statement is issued.  The Inspection Statement is not to be taken as implying a satisfactory state of affairs in documentation, premises, equipment, personnel or procedures not examined during the inspection. 

Following the presentation at the GCP Seminar in October 2006 on providing suitable responses to GCP inspection findings, a guidance document can be found below:
› Guidance for formulating responses to GCP inspection findings (29Kb)

Critical findings are routinely referred to the MHRA’s Clinical Trial Inspection Action Group (CTIAG), a non-statutory, multi-disciplinary group constituted to advise the Director, Inspection & Standards, the Director, Post-Licensing and the Director, Licensing on any recommendation for referral or enforcement action appropriate to the Divisions, which arises from non-compliance detected during GCP inspections. CTIAG provides advice in cases where critical findings are identified during inspection and/or serious non-compliance is identified that could affect the rights, safety or well-being of trial subjects.

Triggered inspections
Triggered inspections differ from our routine systems based inspections in that generally the objectives of the inspection are to answer specific questions raised or to satisfy the MHRA that a specific trial has been conducted in accordance with legislation stated above.  The inspection activities at site will be similar, but these inspections can be unannounced and a plan may not be shared with the organisation.

How to report breaches of GCP or the trial protocol
Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 [Statutory Instrument 2004/1031], as amended by Statutory Instrument 2006/1928, contains a requirement for the notification of "serious breaches" of GCP or the trial protocol. We have issued the following guidance on the notification of serious breaches of GCP:
› Guidance for the notification of serious breaches of GCP or the trial protocol (245Kb)

This guidance:

  • outlines the practical arrangements for notifications
  • provides advice on what should and what should not be classified as a “serious breach” and what must be reported
  • outlines possible actions that may be taken by the MHRA in response to notifications of serious breaches.

What rights do GCP Inspectors have?
Inspectors have rights conferred under the Medicines Act sections 111(1 to 3) and 112 (1 to 4 and 7) as well as subordinate legislation applying the Act, primarily the Statutory Instrument 2004:1031 The Medicines for Human Use (Clinical Trials) regulations 2004.  These include the right to enter any premises involved in clinical trials of investigational medicinal products to carry out inspections, take samples, require the production of books and documents, and to take copies of, or copies of entries in, such books and document and seize and detain substances, articles and documents. It is a criminal offence under section 114 (2 and 3) of the Medicines Act 1968 to obstruct an Inspector during the conduct of an inspection covered by the Act.

How is the MHRA GCP Inspectorate organised?
An organogram for the GCP Inspectorate can be viewed here.
› GCP Organogram (373Kb)

Who does the GCP Inspectorate report to?
The Inspectorate reports to Gerald Heddell, Director of the Inspection & Standards (I&S) Division.  Mr Heddell is a member of the MHRA’s Executive Board which reports to Department of Health Ministers via the MHRA’s Agency Board.

Where is the GCP Inspectorate located?
The GCP Inspectorate operates from three locations:

  1. GCP Inspectorate, MHRA, Market Towers, 1 Nine Elms Lane, London, SW8 5NQ, telephone 020 7084 2606, fax 020 7084 3519.
  2. GCP Inspectorate, MHRA, 2 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW, telephone 01707299130, fax 01707 376649.
  3. GCP Inspectorate, MHRA, 2a Hunter House, 57 Goodramgate, YORK, YO1 7FX, telephone 01904 610556, fax 01904 625430.

GCP inspection fees
Organisations that are inspected are charged a fee according to the size of the inspection undertaken.

The current level of fees payable can be found by visiting our Fees for licensing medicines section.

Phase I Accreditation Scheme
Following the TGN1412 incident in March 2006, where six clinical trial subjects became seriously ill and were admitted to intensive care, an Expert Scientific Group (ESG) was formed to review Phase I clinical trials.  One of the recommendations from the ESG was to establish a national accreditation system for First in Human (FIH) studies. The MHRA have developed such a scheme in order to maximise subject safety and to create additional public confidence in the regulatory oversight of such trials. The development of the scheme has involved wide consultation with representatives from industry associations, academia, NHS, Department of Health, Ethics Committees, the Faculty of Pharmaceutical Medicine and the UK Resuscitation Council. In addition, the opinion of the Commission on Human Medicines (CHM) and also the Expert Advisory Group of the CHM has been sought. A public consultation exercise (MLX 341) took place which ended on 12 October 2007. The proposal has been revised to reflect these comments and we are now in a position to implement the scheme. We also plan to reconvene the consultative committee to review the scheme approximately six months following implementation.

The summary of responses to the public consultation and the final Phase I Accreditation Scheme document, along with the application form, for those units wishing to apply for accreditation are available below:

› Phase I Accreditation Scheme (66Kb)
› Phase I Accreditation Scheme - Application form (815Kb)
› Responses to public consultation of the Phase I Accreditation Scheme October 2007 (36Kb)

External links
(The MHRA is not responsible for the content of external internet sites.)

GCP information
The following contains responses to the questions received at the GCP Non-Commercial Symposium on the 24 September 2007 at the Royal York Hotel, York.

› Response to symposium questions (42Kb)

Contact for further information
For further information on this part of our site, please contact either:

  1. GCP Inspectorate, MHRA, Market Towers, 1 Nine Elms Lane, London, SW8 5NQ, telephone 020 7084 2606, fax 020 7084 3519
  2. GCP Inspectorate, MHRA, 2 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW, telephone 01707299130, fax 01707 376649
  3. GCP Inspectorate, MHRA, 2a Hunter House, 57 Goodramgate, YORK, YO1 7FX, telephone 01904 610556, fax 01904 625430
  4. E-mail info@mhra.gsi.gov.uk

The office is staffed from 9.00am to 5.00pm. Outside these hours a voice mail system is in operation.

Provision of advice to those involved in research and to other regulatory agencies: in order to receive a written response, GCP queries should be forwarded to the GCP Inspectorate in writing.

 


Page last modified: 27 November 2008