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- Written Informed Consent
- Consent in Clinical Trials involving Incapacitated Participants
- Safety Reporting
- GCP Monitoring
- Substantial Amendments
- Addition of New sites
- Serious Breaches
- Progress Reports-Ethics, NHS Trust R&D and MHRA
- Early end/temporary halt to trial
Written Informed Consent
- Informed consent is at the heart of ethical research;
- Informed consent should be freely given and each participant should be fully informed;
- Informed consent must be obtained from every trial participant;
- Informed consent is a process by which a subject voluntarily confirms willingness to take part in a trial, after having been informed of all aspects relevant to their decision to participate;
- Informed consent should be documented on a consent form.
Written and verbal versions of the information will be presented to the subject detailing no less than:
- the exact nature of the study;
- the implications and constraints of the protocol;
- the known side effects and any risks involved;
- that they are free to withdraw from the study at any time for any reason without prejudice to future care, and with no obligation to give the reason for withdrawal.
They must be allowed as much time as wished to consider the information, and to question the investigator, their GP or other independent parties. Consent will be recorded on a consent form signed and dated by the participant and the person who presented informed consent. A copy of the signed form will be given to the subject.
Persons taking informed consent must be appropriately trained and authorised to do so by the Chief/ Principal Investigator. The study team should be aware that the participant information sheet should, at all times, reflect the full information available for the study. Any new information should be promptly addressed in an amendment submitted to the relevant Research Ethics Committee (REC), MHRA and R&D department and copied to CTRG. A SOP Template for Informed Consent (58kb) is available.
Consent in Clinical Trials involving Incapacitated Participants
The Medicines for Human Use (Clinical Trials) Regulations 2004 allows for inclusion of incapacitated adults in a clinical trial as long as inter alia, i) consent is given by a legal representative on behalf of the participant; ii) the trial relates directly to the condition from which the participant suffers; and iii) the benefits outweigh the risks or produce no risk at all.
The Medicines for Human Use Clinical Trials Amendment (No 2) Regulations 2006 (PDF file, 44 KB) allows for inclusion of incapacitated adults in emergency research without consent by their legal representative if i) treatment is required urgently ii) the nature of the trial is such that urgent action is essential e.g. clinical trials in emergency care settings; (iii) obtaining consent from a legal representative is not reasonably practicable and iv) an ethics committee has given approval.
The Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 (PDF file, 56 KB) which came into force on 1 May 2008 extends the exception to minors as clinical trial participants.
Safety reporting is an essential aspect of the conduct of a Clinical Trial and it is important to understand the issues involved and the legal requirements for this. You must be able to readily define, recognise and know the reporting requirements. You should be able to define the following:
- Adverse Events (AE),
- Adverse Reactions (AR)
- Serious Adverse Events (SAE)
- Serious Adverse Reactions (SAR) and
- Suspected Unexpected Serious Adverse Reactions (SUSAR)
Details of these are outlined in the SOP Template for Safety Reporting (96kb), which you can adopt if needed. CTRG staff are happy to provide basic training on safety reporting, but it is your responsibility to ensure that you fully understand this matter.
The overall responsibility of reporting lies with the Sponsor. However, this responsibility may be delegated to the Chief Investigator who will have specialist knowledge of the disease area and the medicinal product being investigated. On behalf of the University, CTRG staff will undertake a risk assessment to assess the level of delegation. If a committee is in place to review Serious Adverse Events (SAE), then responsibility may be fully delegated, CTRG requiring only that they receive a copy of the Development Safety Update Reports (DSURs).
Otherwise SAEs can be reviewed by the Trials Safety Group, a joint body of the Oxford University Hospitals NHS Trust and the University. In such cases CTRG will need to be notified of SAEs within one working day of awareness of the SAE.
If you need to report a Serious Adverse Event (SAE), a Serious Adverse Events Reporting Form for CTIMPs (103kb) can be printed, signed and emailed or faxed to CTRG. Please refer to the Serious Adverse Events Reporting Form Completion Guidelines (61kb).
The Regulations require that Clinical Trials be adequately monitored for GCP compliance. However, the monitoring of non-commercial trials does not always need the intensity traditionally employed by the pharmaceutical industry. CTRG may be able to provide monitoring, or help you find an appropriate monitor. It is essential for the costs of monitoring to be included in funding applications. Monitors must be qualified and adequately trained.
Where the University is the research sponsor CTRG review and approve all amendments to protocols before submission to regulatory bodies. This is essential to ensure that indemnity is not affected by the change(s).
A protocol amendment for changes to the research after approvals from the REC, MHRA and/or R&D department have been received. If the amendment requires immediate implementation due to safety concerns (Urgent Safety Measures) - this should be discussed with the MHRA as soon as possible and a formal amendment must be submitted within 3 days.
In all other cases the REC, MHRA, sponsor and relevant R&D department must approve substantial amendments, before they are implemented. A substantial amendment is defined as an amendment to the terms of the protocol or any other supporting documentation that is likely to affect to a significant degree:
- the safety or physical or mental integrity of the subjects of the trial
- the scientific value of the trial
- the conduct or management of the trial
- the quality or safety of any investigational medicinal product used in the trial
Non-substantial amendments must be approved by the sponsor as many will affect indemnity, but they do not need to be notified to the REC or MHRA. However, records of the amendment and when it was implemented should be kept in the Trial Master File.
CTRG has an SOP Template for Preparation and Approval of Protocol Amendments (59kb) that you can adopt/adapt for this purpose.
Addition of New sites
Addition of new sites, or a change in the Principal Investigator at an existing site, in a Clinical Trial is a substantial amendment as it changes the conduct or management of the trial. You will also need to have agreements in place for the conduct of the trial at those sites. Medical Research Services will assist you with this.
In the event that a serious breach is suspected CTRG must be contacted as a matter of urgency as the sponsor is required to report serious breaches within 7 days.
CTRG can provide information on what should, or should not, be classified as a serious breach and on the practical arrangements for notifications.
The Medicines for Human Use (Clinical Trials) Regulations define 'serious breaches' as any serious breach of
- "(a) the conditions and principles of good clinical practice in connection with that trial; or
- (b) the protocol relating to that trial, as amended from time to time in accordance with regulations 22 to 25, within 7 days of becoming aware of that breach.
For the purposes of this regulation, a "serious breach" is a breach which is likely to affect to a significant degree
- (a) the safety or physical or mental integrity of the subjects of the trial; or
- (b) the scientific value of the trial."
Progress Reports-Ethics, NHS Trust R&D and MHRA
Development Safety Update Reports
The Development Safety Update Report is required to be submitted to MHRA and REC on the anniversary of the ‘International Birth Date of your IMP - that is the first issue of a Clinical Trials Authorisation (CTA) for that IMP.
Guidance is available from CTRG and on the MHRA website.
Annual Progress Reports
A progress report should be submitted to the REC that gave a favourable opinion 12 months after the date on it was given, and annually thereafter until the end of the study. A copy must be sent to CTRG and the relevant NHS Trust.
Early end/temporary halt to trial
If the trial is terminated prematurely or temporarily, it is the responsibility of the Chief Investigator (on behalf of the Sponsor) to notify the MHRA and REC within 15 days explaining why, using the End of Trial Form.
Please inform CTRG promptly of any such suspension or early end. This applies to any trial terminated early even if no participants have been recruited.