Clinical Trials

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The Legal Framework

Regulation Through the Decades

The Medicines Act 1968

The Medicines Act 1968 Schedule S58 (2) 6 permits a person acting in accordance with the directions of an appropriate practitioner (doctor or dentist) to administer a licensed medicinal product. This legislation was introduced to protect the public from the harm that could be caused by the inappropriate use of medicines with marketing authorisation.

The Main Legislation

Two main pieces of legislation control the sale, supply and administration of medicines namely:

• The Medicines Act 1968 which controls Prescription only Medicines (POMs)
• The Misuse of Drugs Act 1971, which regulates Controlled Drugs.

For investigational medicinal products involved in clinical trials, there was no formal legislation, just guidance.

The World Medical Association; The Declaration of Helsinki.

In 1945 the World Medical Association was formed to represent physicians worldwide. The aim of this non political body was to address non clinical medical issues.

 In 1964 The Declaration of Helsinki was written and is a statement of ethical principles developed by the World Medical Association to:

"provide guidance to physicians and other participants in medical research involving human subjects"  (Para 1, Declaration of Helsinki).

This includes research on people, identifiable human material or identifiable data.
The Declaration was first adopted in 1964 and has since undergone several revisions to accommodate advances in medical science and ethical problems. The last revision being in 2004, in Tokyo, by the World Medical General Assembly.

The Declaration of Helsinki includes principles on:

• safeguarding research subjects
• informed consent
• minimising risk
• adhering to an approved research plan/protocol

'The Declaration' is considered a  fundamental document in the  ethics of healthcare research.  As a result, the principles have been embodied in subsequent UK and international guidance and regulations.

The EU Directive 2001/20/ECGood Clinical Practice in Clinical Trials

Background

Research Governance is the legal, and regulatory framework for research within the healthcare community.  This policy from the Department of Health (DOH) sets out the duties and responsibilities of investigators, secondary care (Care organisations) and sponsors and funders of clinical research.  Central to ‘Research Governance’ is the EU Directive 2001/20/EC Good Clinical Practice in Clinical Trials which covers the conduct of clinical trials. 

This piece of legislation applies to non-commercial (Research Council, Charity-funded) trials the same standards of quality that have applied to commercial trials (funded by pharmaceutical companies) for the last 10 years.  The standards are summarised in the ICH/GCP guidelines (Good Clinical Practice).   

In 2001 The EU Directive 2001/20/EC (that took over 10 years to prepare) a Directive from the European Parliament and Council, came into force and was adopted (4th April 2001).

This Directive applied to research designed to ascertain or confirm the safety and/or efficacy of medicinal products involving clinical intervention conducted according to a research protocol.

This legislation applied to member states in Europe and had to be consulted on in the UK and so in 2003, MLX287 was distributed by the MHRA for consultation.

The legislation was to be transposed into national law by member states by May 2003 and implemented in Europe by May 2004.

In 2003-2004 transitional arrangements were honoured and because the EU Directive required adoption of the principles of Good Clinical Practice, the Commission published guidelines in the form of a subsidiary Directive.

Implementation of the EU Directive 2001/20/EC

On 1st May 2004 the Member States implemented the EU Directive Clinical Trials 2001/20/EC.

The UK legislation went before Parliament in April 2004 and became effective in May 2004. Up until this time the UK legislation had been The Medicines Act 1968 and any associated statutory instruments. Every clinical trial involving a medicinal product, except where they are deemed to be ‘non interventional’ (i.e. where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation (see Article 2c) and are deemed to be ‘current practice’) was to be covered by this new legislation, whether the trial was sponsored by industry, the government, a research organisation, a charity or a university. The other exception was that any additional diagnostic or monitoring procedures related to therapeutic strategy were not to be used for analysis or collection of the data).

Further Legislation

There was a delay in the acceptance of the EU Directive in the UK. This was to allow further consideration of concerns expressed by the academic research community about the possible impact of the Directive and to allow two Commission Directives to be finalised that dealt with Good Manufacturing Practice (GMP)(2003/94/EC) and Good Clinical Practice (GCP) (Still outstanding, however ICH Tripartite Guidelines for Good Clinical Practice (1996) are available).

The implementation of the EU Directive 2001/20/EU in the UK, was in the form of UK Medicines for Human Use (Clinical Trials) Regulations 2004  in other words, the document that implemented the EU Directive in the UK.

The UK Medicines for Human Use (Clinical Trials) Regulations 2004

The introduction of the EU Directive 2001/20/EC which had been under development since 1991 was to change the way that clinical trials were conducted.  The new regulations that were published in 2001 meant that all clinical trials involving medicinal products  were to be regulated : commercial and non - commercial clinical trials; from Phase 1 clinical trials  to trials those in the later stages of testing and included some medicines  which were already marketed, but the effect of which would be monitored during the trial.

The EU Directive would   ensure that the rights, safety and well-being of those participating in clinical trials (including incapacitated adults and minors) were protected. Informed consent was a specific issued given due consideration for these groups of individuals.

Also encompassed by the new legislation was:

• standardisation of procedures for ethical and competent authority consideration (e.g.MHRA’s role and timelines for ethical review
• the setting of Good Clinical Practice (GCP) standards for commencing and conducting clinical trials
• the setting of Good Manufacturing Practice (GMP) for the preparation of medicinal products involved in clinical trials
• the requirement for inspections by the MHRA, against internationally accepted principles and standards of GCP and GMP, supported by the powers of enforcement.

The main reason for the move to introduce formal legislation from previous ‘guidance’ was to ensure that patients were protected and to ensure that clinical trials produced valid data. The Directive did this by enforcing a new ‘legal’ structure, imposing standards for the manufacture, labelling, importing and the quality assurance of medicinal products involved in clinical trials.

Some of the changes encompassed:

• the regulation of healthy volunteer studies by the MHRA, with timelines of 14 days with the ability to extend to 21 days if required

• authorisation of the clinical trial by the competent authority (MHRA, who acts on behalf of the Licensing Authority under the Medicines Act 1968 ), rather than control of the Investigational Product- Clinical Trial Authorisation (CTA) required before commencing a clinical trial. One CTA per trial that includes all IMPs, rather than control of each CTIMP . The deadline for consideration by the Licensing Authority being 30 days with in certain cases the ability to extend to 60 days.

• the need for clinical trials to comply with Good Clinical Practice (GCP)

• the need for the establishment of ethics committees on a legal basis with imposed legal obligations in relation to certain procedures e.g. timescales in which a favourable opinion must be given (60 day time limit for decisions, with extensions  for trials involving gene therapy with no time limit for the consideration of xenogenic cell therapy trials)

Other requirements were that :

• products are manufactured and produced according to Good Manufacturing Practice (GMP), Manufacturing licence requirement
• manufacturers/importers to hold appropriate manufacturer’s authorisation
• the manufacturer or importer must have a Qualified Person available (QP) (Article 49 Directive 2001/83/EC

• medicines Involved in clinical trials are labelled according to Good Manufacturing Practice (GMP) (Annex 13 of Directive), this includes placebo medication and active comparator products
• there are processes and procedures in place to ensure the recording of any suspected adverse events/incidents

Ensuring Compliance with the Legislation

To ensure compliance with the new legislation processes for formal inspections of GCP and GMP by the regulatory agency (MHRA) were also introduced (Article 15). The inspections will take one of the two forms:

• cyclical, systems based inspections.
• triggered inspections (as required)

As were processes for the monitoring of patients and the reporting and recording of adverse reactions and events. (Pharmacovigilence)

To ensure good communication networks and monitoring of clinical trials
Secure networks were established linked to European databases (e.g. Eudract Database)

For further information please access the documents at the links above.

 

 

 

 

 

 

 

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