Summary of Clinical Trial Regulations for Investigators
This summary should be used as guidance only. It is recommended that you view the full Medicines for Human Use (Clinical Trials Regulations) 2004
Part 1-Introductory Provisions
‘Chief Investigator (CI)’ for a clinical trial means the investigator for a single trial site or if the clinical trial is held at more than one site, it is the authorised health professional, whether or not s/he is an investigator for any particular site, who takes primary responsibility for the conduct of the trial.
‘Clinical trial’ means an investigation in human subjects, other than a non- interventional trial, which is intended to:
i) discover or verify the clinical, pharmacological or pharmacodynamic effects of the medicinal products;
ii) identify any adverse reactions to those medicinal products;
iii) study absorption, distribution, metabolism and excretion of one or more such products ;
with the objective of ascertaining the safety or efficacy of those products.
‘Health professional’ means a doctor, a dentist, a nurse, or a pharmacist.
‘Investigational Medicinal Product (IMP)’ means a pharmaceutical form of an active substance or placebo being tested, or to be tested, or used, as a reference in a clinical trial, and includes a medicinal product which has a marketing authorisation but is, for the purposes of the trial:
i) used or assembled in a way different from the form of the product authorised under the authorisation;
ii) used for an indication not included in the summary of product characteristics under the authorisation for that product, or;
iii) used to gain further information about the form of that product as authorised under the authorisation.
‘Third Country’ means a country or territory outside the European Economic Area.
Sponsor of a clinical trial
Regulation 3: This defines Sponsor of a clinical trial as the person/organisation who takes responsibility for the initiation, management and financing (or arranging financing) of that trial. If two or more persons take responsibility for carrying out functions, they will have joint responsibility or they may allocate different responsibilities amongst themselves. E.g. roles include obtaining authorisation, conduct of clinical trials and pharmacovigilance.
The University is vicariously liable for the acts or omissions of its employees. Therefore individuals employed by the University should not agree to act as Sponsor. Requests for the University to act as Sponsor should be made to the Research Governance Team in RACD.
Responsibility for functions under the Directive
Regulation 4: This states that the competent authority for the UK is the Medicines and Healthcare Regulatory products Agency (MHRA).
Part 2- Regulations for Ethics Committees.
For further information please refer to the full regulations
Part 3- Authorisation for clinical trials and ethics committee opinion
Interpretation of Part 3
Regulation 11: A substantial amendment to clinical trial authorisation means an amendment to the clinical trial authorisation which is likely to affect to a significant degree, the safety, physical and/or mental integrity of the subjects, the scientific value of trial, the conduct or management of the trial and the quality and safety of the IMP.
Requirement for authorisation and ethics committee opinion
Regulation 12: An individual cannot start, conduct, recruit or issue an advertisement for the purpose of recruitment to a clinical trial unless the MHRA and an ethics committee have given a favourable authorisation/opinion for the trial to commence.
Supply of Investigational Marginal Products for the purpose of clinical trials
Regulation 13: An individual cannot sell or supply an IMP to anyone involved in the trial unless certain conditions are met. Products without a UK valid marketing authorisation which are not made in the UK must meet certain quality testing requirements. Products manufactured or imported prior to 01st May 2004, and products sold or supplied in accordance with a marketing authorisation in the UK, are exempt from some or all of these conditions.
Application for ethics committee opinion
Regulation 14: An application for ethics committee opinion must be made by the CI. Only one approval is required regardless of the number of trial sites.
Ethics committee opinion
Regulation 15: This explains the process for an ethics committee to consider an application and the matters the ethics committee considers in preparing its opinion. If a clinical trial involves a minor or someone who is physically or mentally incapable of giving informed consent, an expert will be consulted. A decision will be made within: 180 days from receipt of application if a specialist group is consulted; 90 days where there is no consultation and the study involves a medicinal product for gene therapy; or 60 days in all other cases.
Review and appeal relating to ethics committee opinion
Regulation 16: If an ethics committee does not give a favourable opinion, the CI may appeal within 90 days of being notified by the committee. Where the opinion was given by the Gene Therapy Advisor Committee, the CI can appeal within 14 days of receiving opinion in writing. The Gene Therapy Advisory Committee has 60 days to review its opinion.
Request for authorisation to conduct a clinical trial
Regulation 17: To conduct a clinical trial, authorisation must be obtained from the MHRA. This must be in writing, signed by, or on behalf of the Sponsor and be accompanied with the necessary documentation.
Authorisation procedure for clinical trials involving general medicinal products
Regulation 18: Within 30 days of receipt of an authorisation request, the MHRA will either issue an authorisation, an authorisation subject to conditions or a rejection. If no notification is received within 30 days, the trial is treated as authorised. If rejected, the Sponsor may within 14 days, submit an amendment request to MHRA. The MHRA must review and provide an outcome within 60 days of the original authorisation request. If the amendment is not accepted, the MHRA will not consider any additional amendments.
Authorisation procedure for clinical trials involving medicinal products for gene therapy
Regulation 19: This governs the authorisation procedure for clinical trials involving products for gene therapy and somatic cell therapy or medicinal products containing genetically modified organisms. Within 30 days of receiving an authorisation request, the MHRA will grant approval, approve subject to changes or reject. In some circumstances the MHRA may wish to consult a specialist committee before it issues authorisation for the trial and, if this is the case, the MHRA specified period will be extended by 90 days. If the MHRA issues authorisation subject to changes, amended requests can be made by the Sponsor within 30 days of receiving notification. The MHRA will consider the amendment request within 90 days, or, if the specialist committee is consulted, within180 days.
Authorisation procedures for clinical trials involving medicinal products with special characteristics.
Regulation 20: This governs the authorisation procedure for clinical trials involving medicinal products which are ‘high technology’ products subject to licensing by the European Medicines Agency, biological medicinal product or other medicinal products which have special characteristics. Within 30 days of receiving authorisation request, the MHRA will issue written authorisation. If authorisation is not granted CI may appeal and submit an amendment request within 14 days. The MHRA will consider the amendment and, no later than 60 days from receipt of original request it will authorise or reject.
Clinical trials conducted in third countries
Regulation 21: If a clinical trial has a site that is located in a third country as well as the UK, the MHRA requires that site to permit its premises to be inspected by or on behalf of the MHRA to ensure trial sites are compliant with Good Clinical Practice (GCP).
Amendment to clinical trial authorisation
Regulation 22: Amendments to a clinical trial authorisation may be made by the MHRA or the Sponsor.
Amendments by the MHRA
Regulation 23: Amendments may be made by the MHRA to ensure safety and scientific validity and to ensure there is adherence to the principles of GCP. The MHRA will inform the Sponsor 14 days before the proposed amendment is to take affect stating its proposed amendments and reasoning. The Sponsor may make representations in writing within these 14 days.
Amendments by the Sponsor
Regulation 24: The Sponsor may make a non-substantial amendment to a clinical trial at any time and is required to keep a list of all amendments made during that trial. However, if the Sponsor proposes to make a substantial amendment, the MHRA and ethics committee will need to be notified. Within 35 days, the MHRA and ethics committee will give written notice and specify the reasons for accepting/ not accepting the amendment. The amendment may only be made when the MHRA and ethics committee have granted approval.
Modifying or adapting rejected proposals for amendments
Regulation 25: If the MHRA and/or ethics committee give an unfavourable opinion, the Sponsor can amend the protocol and notify the MHRA and/or ethics committee 14 days before the proposed amendment is to be made. Within 14 days of receipt of the proposed amendment, the MHRA and ethics committee will give its written opinion to the Sponsor stating approval/ non-approval. If no notice is received from MHRA, the amendment may be made.
Reference to the appropriate committee or the Medicines Commission
Regulation 26: If the MHRA or ethics committee reject or impose conditions on the authorisation, the sponsor has 28 days to appeal and give notice in writing of its wish to make written or oral representations.
Conclusion of a clinical trial
Regulation 27: The Sponsor must notify the MHRA and ethics committee in writing within 90 days of when the trial has ended. If the trial is terminated before the date for the conclusion of the trial specified in the protocol, the Sponsor must notify the MHRA and ethics committee within 15 days, stating reasons for termination.
Part 4- Good Clinical Practice and the conduct of Clinical trials
Good Clinical Practice and protection of clinical trial subjects
Regulation 28: An individual must not conduct a clinical trial or perform functions of the Sponsor other than in accordance with the principles of GCP and the Sponsor must have arrangements in place to ensure this. The Sponsor must ensure that IMP and devices used for the administration of IMPs, are made available free of charge, to trial participants except for prescription and other NHS charges. If the trial is conducted at more than one site, the Sponsor may delegate responsibility for duties to an appropriate individual at a specific site.
Conduct of trial in accordance with clinical trial authorisation etc
Regulation 29: An individual must not conduct the trial other than in accordance with: the protocol; the terms of the request for authorisation from the MHRA; and with the ethics committee opinion.
Urgent safety measures
Regulation 30: The Sponsor and investigator may take appropriate urgent safety measures in order to protect trial participants against any immediate harm to their health and safety. In such cases, the Sponsor should inform the MHRA and the ethics committee by written notice within 3 days of the event occurring.
Suspension or termination of clinical trial
Regulation 31: The MHRA has the authority to suspend or terminate a clinical trial if it has concerns regarding its conduct, safety or scientific validity. One week prior to issuing a notice of suspension or termination, the MHRA will notify the Sponsor/ investigator of the reasoning for this. Within 28 days, the sponsor may make written or oral representations to the Committee on Safety of Medicine (also known as the Medicines Commission.)
Part 5- Pharmacovigilance
Notification of adverse events
Regulation 32: An investigator is responsible for reporting all Serious Adverse Events (SAE) immediately to the sponsor orally or in writing (except those identified in the protocol or investigator brochure as not requiring immediate reporting.) Afterwards the investigator must submit a detailed report. The Sponsor will keep detailed records of all reported adverse events relating to a clinical trial
Notification of suspected unexpected serious adverse reactions (SUSAR)
Regulation 33: The Sponsor must ensure that any SUSAR which is fatal or life-threatening is recorded and reported to the MHRA and ethics committee within 7 days of when the Sponsor was first aware of the SUSAR. Within 8 days of a report, any additional relevant information should be sent to the MHRA. If non-fatal or life-threatening SUSARs occur, the Sponsor must notify the MHRA and relevant ethics committee within 15 days. The Sponsor may fulfil its reporting obligations by entering the information into the European pharmacovigilance database. The Sponsor must ensure that all investigators are informed of any SUSARs that have occurred in relation to an IMP that is being used in that clinical trial.
Trials conducted in third countries
Regulation 34: The Sponsor must enter relevant information on SUSARs into the European pharmacoviligance database when they occur at a trial site which is located outside the UK.
Annual list of suspected serious adverse reactions and safety report
Regulation 35: For each IMP tested, the Sponsor must provide the MHRA and ethics committee with a list of suspected serious adverse reactions that have occurred in its trial and provide a report on the safety of those participants in that trial.
Part 6- Manufacture and Importation of IMP
Requirement for authorisation to manufacture or import IMP
Regulation 36: An individual must not manufacture, assemble or import any IMP except in accordance with a manufacturing authorisation unless the product has a marketing authorisation.
Exemption for hospitals and health centres
Regulation 37: Exemption from Regulation 36. This exemption applies where a hospital or health centre holds manufacturing authorisation to assemble an IMP, when the “assembly” is carried out by a doctor or a pharmacist, or under the supervision of a pharmacist. “Assembly” is related to packaging and labelling and not to the preparation of medicines from their ingredients. The exemption applies only if the product is to be used exclusively in that hospital or health centre or any other that is a trial site for the clinical trial in which the product is to be used.
Regulations 38-45. These set out the application, variation and suspension process, for applying for a manufacturing authorisation and the definition of a ‘Qualified Person’.
Part 7: Labelling of Investigational Medicinal Products
Regulation 46: An IMP should be labelled in accordance with requirements of the Commission Directive 2003/94/EC(a) on Good Manufacturing Practice. Label must ensure protection of trial subjects, identification of product and trial, and assist proper use of the product.
Part 8: Enforcement and related provisions
For further information please refer to the full Regulations
Part 9 -Miscellaneous Provisions
For further information please refer to the full Regulations