Department of Health
Market Towers 1 Nine Elms Lane London SW8 5NQ
Telephone 0171-273 0642
Facsimile 0171- 273 0286 .
6 August 1999

Dear Mr Medawar,

Thank you for your letter of 17 June to the Secretary of State for Health. As you know that letter has been passed to the Medicines Control Agency (MCA) for reply.

Dr Bohaychuk has produced a useful editorial that identifies the importance of developing a legislative framework for the application of Good Clinical Practice (GCP) in the conduct of clinical trials. We expect to have a legal basis for compulsory inspection for GCP when the proposed EU Directive on Good Clinical Practice in the Conduct of Clinical Trials [1] is incorporated into EU law and then into UK legislation. The draft Directive is still under discussion in Europe. The UK has been active in those discussions but there is as yet no clear timetable for its adoption. Our position is that the UK welcomes the intention to enshrine GCP in legislation.

Perhaps I could usefully begin by describing the controls that are currently in place on the conduct of clinical trials on medicines in the UK. Anyone wishing to conduct such a clinical trial is required to submit an application to the MCA. The Medicines Act 1968 definition of a clinical trial does not include "healthy volunteers" studies, involving the administration of a medicine with no expectation of benefit to the recipient, in contrast to clinical trials, in which medicines are administered to patients with some expectation of improvement in their condition. The Act gives the MCA the power to stop trials or to amend protocols because of safety considerations.

The application to conduct a clinical trial must include scientific evidence to support the quality and safety of the medicine, together with a protocol setting out the arrangements for the conduct of the trial. On the basis of the summary information supplied, the MCA either exempts the applicant from the need to hold a certificate, or requests more detailed information to allow a full assessment of the application. In the latter case if the trial is approved, a certificate will be issued to the applicant. This applies to all clinical trials of medicines in the UK and anyone who does not comply is liable to prosecution. Relevant ethics committees must also assess and approve such trials before they can begin. Any significant changes to the protocol for a clinical trial (such as a change in dose of medication, or numbers of patients to be enrolled in the trial) must be submitted to the MCA and to the relevant ethics committee for approval.

A key condition of approving a clinical trial is the requirement placed on the "sponsor",[2] to notify the Agency of all serious adverse reactions to the trial medicine. The standards and timeframes for such reports are published in a guideline [3] agreed between the EU, USA and Japan at the International Conference on Harmonisation (ICH). This has been in operation in the EU since June 1995. Adverse reaction reports are assessed by the MCA to identify possible drug safety issues and if necessary appropriate action can then be taken to protect trial subjects. The responsibility for the proper conduct of the trial, for the safety and care of the trial subjects and for notifying adverse reactions and any other information relevant to the approved protocol rests with the sponsor of the trial.

The expected standards and ethical principles required during the conduct of clinical trials were also agreed between government officials and representatives of the pharmaceutical industry at the ICH. These are widely available in a further published guideline [4] that was implemented by the European Community in 1997. This guideline [5] states that ethics committees have a responsibility to safeguard the rights, safety and well-being of all trial subjects. The guideline also states that ethics committees should conduct a continuing review of each on-going trial. In practice this means that ethics committees receive information about the progress of the study such as protocol amendments (which may require approval by the committee), safety reports (copies of serious and unexpected adverse reaction reports), annual progress reports (if the study lasts more than a year) and an end of study report.

The MCA established a GCP Compliance Unit in 1996 to inspect sites conducting clinical trials. The Compliance Unit's main roles are to evaluate whether:

*the trial was conducted and the data were recorded, analysed and accurately reported in accordance with applicable guidelines (eg. ICH GCP) and regulations.

* the systems used by sponsors/contract research organisations to conduct trials and analyse and report trial results, assure compliance with applicable guidelines (ICH GCP is used as the main reference) and regulations.

Turning now to the specific questions you raise:

Q1 whether or not the evidence available to the MCA broadly supports or refutes these published [Wendy Bohaychuk] audit findings.

Evidence is not available in a form that can be used to support or refute these audit findings.

Q2 How many GCP audits has the MCA itself carried out to date and what plans, if any, the Agency has for expanding its work in this field?

Since the GCP inspection programme commenced in 1997 and up to now, there have been

By the end of 2000 we plan to have conducted around another 35 inspections of facilities in the UK. Once the proposed EU Directive [6] on GCP is introduced into UK law, the GCP inspection programme will have a mandate to undertake inspections without invitation. The Directive will apply to all clinical trials, with the exception of what the current draft describes as "noninterventional trials" [7]. It envisages that GCP inspections will not only be conducted for trials sponsored by the pharmaceutical industry, but also for trials sponsored by other research organisations (e.g. the Medical Research Council, medical charities, the National Health Service and individual doctors).

Q3 Whether and to what extent independent evidence of levels of non-compliance with GCP is at present routinely scrutinised by the MCA (or CSM), as part of the process of examining Product Licensing applications?

The Committee on the Safety of Medicines (CSM) does not scrutinise independent evidence (by which I assume you mean articles similar to that published by Ms Bohaychuk) of alleged non-compliance with GCP guidelines. Compliance with appropriate standards and requirements is the responsibility of the trial sponsor and, if invited to inspect, of the GCP Compliance Unit. However, the Compliance Unit does not conduct GCP inspections in relation to every licensing application submitted to the MCA. If, during a GCP inspection, evidence is discovered which relates to the quality and/or integrity of clinical trial data intended for inclusion as part of a licensing application, then the Compliance Unit would inform the relevant assessors within the MCA. Since 1992 and in accordance with Directive 75/318 EEC [8], as amended, the Agency has required all phases of clinical investigation to be conducted in accordance with the principles of good clinical practice, and confirmation of this is part of the evaluation of an application for a marketing authorisation.

Q4 Whether the MCA has ever conducted any enquiry into general standards of compliance with GCP and/or the need for auditing by government regulators and, if so, when and what conclusions were reached.

The inspections conducted by the GCP Compliance Unit focus on the systems used by pharmaceutical companies, contract research organisations and others to assure compliance with GCP. An assessment of the standard of GCP compliance is made by the Unit's inspectors during each inspection. GCP compliance standards can vary from company to company and it is too soon for general conclusions to be drawn from the sample of companies that have so far been inspected by the Compliance Unit.

Q5 Whether any sort of disciplinary action had ever been taken against any company or companies arising from non-compliance with GCP and whether any record of such actions is publicly available.

There is no statutory basis for GCP inspection at present and therefore no disciplinary action has been taken against any facility inspected.

Q6 Whether companies are formally required to demonstrate a satisfactory level of compliance with GCP as a condition of granting a product licence?

Sponsor companies are required to include a statement of GCP compliance in any final study reports which are submitted as part of a licensing application. However that statement is not necessarily a demonstration of "a satisfactory level of compliance" as a separate review of compliance may not always have been undertaken by the sponsor or by a contractor employed by the sponsor. As outlined above under question 3, the GCP Compliance Unit does not conduct GCP inspections in relation to every licensing application submitted to the MCA. Additionally, the ICH GCP Guideline (at section 5.19.3) states that "to preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings". The Compliance Unit would, of course, seek such reports if they considered it necessary.

I hope this is helpful.

Yours sincerely
Mrs Anne Thyer
Executive Support



Contents page
List of MCA/CSM Correspondence


1. European Parliament and Council Directive 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.  BACK

2. Sponsor: an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial. (ICH Note for Guidance on Good Clinical Practice ICH-E6).  BACK

3. "Clinical Safety Data Management - Definition and Standards for Expedited Reporting" (ICH - E2A).  BACK

4. "Note for Guidance on Good Clinical Practice" (ICH - E6).  BACK

5. ICH GCP guideline section 3. 1.1  BACK

6.  see 1 above  BACK

7. The proposed Directive defines a non-interventional trial as "a clinical trial where the selection of subjects or the attribution of medicinal products or the examinations carried out or medical and biological follow-up of subjects fall within current medical practice".  BACK

8. Council Directive 751318 EEC on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products.  BACK

NOTE: the above documents are available from the EMEA