Royal Visits

Changes that you make to your protocol and related documents after the project has been approved are called ‘amendments’.

Amendments may be substantial or non-substantial:

• Substantial amendments involve significant changes to the design and methodology of a research project.
• Non-substantial amendments do not involve significant changes to the design and methodology of a research project.

Definitions of substantial and non-substantial amendments

A substantial amendment is defined as an amendment to the terms of the application, or to 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 study.
• The scientific value of the study.
• The conduct or management of the study.
• The quality or safety of any investigational medicinal product used in the trial.

Examples of non-substantial amendments include:

• Minor changes to the protocol or other study documentation, e.g. correcting errors, updating contact points, minor clarifications.
• Updates of the investigator’s brochure.
• Changes to the chief investigator’s research team.
• changes to the research team at particular trial sites.
• Changes in funding arrangements.
• Changes in the documentation used by the research team for recording study data.
• Changes in the logistical arrangements for storing or transporting samples.
• Inclusion of new sites and investigators.
• Change to the study end date.

For all studies, it is the responsibility of the sponsor to determine whether an amendment is substantial.

A detailed list of substantial and non-substantial amendment examples can be found on the HRA website.

Changes to contact details for the sponsor (or the sponsor’s representative), chief investigator or other study staff are minor amendments but should be notified to the main REC for information.

The Development Safety Update Report (DSUR), also known as the ctIMP Annual Safety Report is intended to be a common standard for periodic reporting on drugs under development (including marketed drugs that are under further study) among the International Conference on Harmonisation (ICH) regions.

US and EU regulators consider that the DSUR, submitted annually, would meet national and regional requirements currently met by the US Investigational New Drug Annual Report and the EU Annual Safety Report, respectively, and will therefore take the place of existing safety reports.

The main objective of a DSUR is to present a comprehensive annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed, by:

• Examining whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the investigational drug’s safety.
• Describing new safety issues that could have an impact on the protection of clinical trial subjects.
• Summarising the current understanding and management of identified and potential risks.
• Providing an update on the status of the clinical investigation/development programme and study results.

For international trials, reference on DSUR production and submission will be detailed in contractual agreements and/or specific protocol documents.

It is the responsibility of the sponsor to send our DSUR reports annually for every ctIMP study to the MHRA and to the main REC.

Research Ethics Committees (RECs) are required to monitor research that has received a favourable opinion. Therefore, researchers must submit Annual Progress Reports in order to inform REC of the progress of the research.

The information required in an Annual Progress Report relates to research conduct, recruitment, amendments, and safety.

A Progress Report should be submitted to the REC (which gave the favorable opinion) 12 months after the date on which the favorable opinion was given. Annual Progress Reports should be submitted thereafter until the end of the study.

How do I submit an Annual Progress Report?

It is the responsibility of the Chief Investigator to complete and submit Annual Progress Reports.

There are separate forms for submitting Annual Progress Reports, depending on the type of research. All forms are available to download directly from the HRA website.

Can I continue with my research after submitting an Annual Progress Report?

The REC does not need to re-confirm its favourable ethical opinion each time an Annual Progress Report is received. It is generally assumed that the opinion applies for the duration of the research, although the REC may review its opinion at any time.

Safeguarding the dignity, rights, safety and wellbeing of research participants must be the primary consideration in any research project, prevailing over the interests of science and society.

The reporting of safety events is one of the most important aspects of clinical trial management and quality control and is now governed by international law.

Safety reporting involves relaying to the appropriate bodies within the required timescales, the occurrence of any harm, suffering or death by a research participant in the course of research. This will permit an assessment of the safety of the research so that measures may be put in place to prevent it happening again. In the most severe cases, the research may be suspended or even terminated.

All participant visits including details of adverse events, clinical tests and investigations must be clearly documented in the patient medical notes and signed and dated.  This information will be transcribed in the Case Report Form (CRF). Clear documentation is essential when running clinical studies.  The need to safeguard confidential and personally sensitive information is vital.

All employees of NBT including temporary staff, students, volunteers and locums are bound by a legal duty of confidence to protect personal information that they may come into contact with. This duty may also be imposed by professional codes of conduct and in the terms of employment contracts or honorary contracts with the trust.

Safety reporting is vital for all research projects; however, there are strict legal requirements to be satisfied in the case of Clinical Trial of an Investigational Medicinal Product (ctIMPs).

Please contact research@nbt.nhs.uk for a copy of our Safety Reporting Flowchart.

Legally, adults must be assumed to be capable of taking decisions unless the opposite has been demonstrated for a particular decision.

Where doubt exists, the chief investigator (CI), principal investigator (PI) or another experienced and independent clinician should formally assess the capacity of the individual to make an informed decision about participation in a research project adhering to North Bristol NHS Trust Mental Capacity Act 2005 decision making flowchart. This assessment and the conclusions should be recorded in the medical records. A participant is deemed to lack legal capacity to consent or refuse only when they cannot be helped to reach their own decisions with memory aids or sign language for example.

The term used in the regulations is “an adult unable to virtue a physical or mental incapacity to informed consent”.

A hierarchy prescribed in the regulations for determining what type of legal representative should be approached to give informed consent on behalf of an incapacitated adult prior to inclusion of the participant in the study. The provisions in England, Wales and Northern Ireland differ from those in Scotland.

The Medicines for Human Use (clinical trials) (Amendment no.2) Regulations 2006 made additional provision relating to trials involving incapacitated adults in emergency situation. Where the treatment to be given to an incapacitated adult as part of the trial needs to be given urgently, time may not allow for the written consent of a legal representative to be obtained first. The amendment allows incapacitated adults to be entered into a trial prior to consent being obtained from a legal representative provided that:

• Having regard to the nature of the trial and the particular circumstances of the case, it is necessary to take action for the purpose of the trial as a matter of urgency.
• It is not reasonably practicable to obtain informed consent prior to entering the participant.
• The action to be taken is carried out in accordance with a procedure approved by the ethics committee.

Where an incapacitated adult is recruited in an emergency situation without prior informed consent, steps must be taken to seek informed consent either from the participant (if capacity has been recovered) or from a legal representative as soon as practicable after the initial emergency has passed.

Where consent is withheld, the participant must be withdrawn from the trial.

Conditions

The legal representative:

• Has had an interview with the investigator, or another member of the investigating team, in which opportunity has been given to understand the objects, risks, and inconveniences of the trial and the conditions under which it is to be conducted.
• Has been provided with a contact point where further information about the trial may be obtained.
• Has been informed of the right to withdraw the participant from the trial at any time.
• Has given informed consent to the subject taking part in the trial.
• May, without the patient being subject to any resulting detriment, withdraw the participant from the trial at any time by revoking the informed consent.
• The participant has received information, according to his or her capacity of understanding, about the trial and its risks and benefits.

In the event of an emergency the above points do not apply

• The investigator must consider the explicit wish of a patient capable of forming an opinion and assessing the information provided. This applies both to the wish of a participant to refuse to take part or to withdraw from the trial at any time.
• No incentives or financial inducements are given to either the participant or to the legal representative, except the provision of compensation for injury or loss.
• There are grounds for expecting that administering the medicinal product to be tested in the trial will produce a benefit.
• The trial is essential to validate data obtained (a) in other clinical trials involving persons able to give informed consent, or (b) by other research methods.
• The clinical trial relates directly to a life-threatening or debilitating clinical condition from which the subject suffers.

Principles

• Informed consent given by a legal representative shall present the presumed will of an incapacitated adult.
• The trial has been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the cognitive abilities of the participant.
• The risk threshold and the degree of distress have to be specially defined and constantly monitored.
• The interests of the participant always prevail over those of science and society.

Under the Regulations a ‘minor’ is a person under the age of 16 years. The regulations prescribe a hierarchy for determining who should be approached to give informed consent on behalf of a minor prior to their inclusion in the trial. 

The provisions for informed consent by a legal representative only apply if by reason of the emergency nature of the treatment provided as part of the trial no person with parental responsibility can be contacted prior to the proposed inclusion of the minor.

• Parent: A parent or person with parental responsibility.
• Personal legal representative: A person not connected with the conduct of the trial who is suitable to act as a legal representative by virtue of their relationship with the minor, and available and willing to do so.
• Professional legal representative: a person nominated by the relevant healthcare provider (eg: an acute NHS Trust) who is not connected with the conduct of the trial.

The Medicines for Human Use (clinical trials) and Blood Safety and Quality Amendment Regulations 2008 made additional provision relating to trials involving minors in emergency situations. Where the treatment to be given to a minor as part of the trial needs to be administered urgently, time may not allow for the written consent of a person with parental responsibility or a legal representative to be obtained first.

The amendment allows minors to be entered into a trial prior to informed consent being obtained provided that:

• Having regard to the nature of the trial and the particular circumstances of the case, it is necessary to take action for the purpose of the trial as a matter of urgency, but, it is not reasonably practicable to do obtain informed consent prior to entering the subject.
• The action to be taken is carried out in accordance with a procedure approved by the ethics committee

Where a minor is recruited in an emergency situation without prior informed consent, steps must be taken to seek informed consent from a person with parental responsibility or a legal representative as soon as practicable after the initial emergency has passed.

Where consent is withheld, the participant must be withdrawn from the trial.

Conditions

• The parent or legal representative has had an interview with the investigator, or another member of the investigating team, in which opportunity has been given to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.
• The parent or legal representative has been provided with a contact point where further information about the trial may be obtained.
• The parent or legal representative has been informed of the right to withdraw the minor from the trial at any time.
• The parent or legal representative has been given informed consent to the minor taking part in the trial.
• The parent or legal representative may, without the minor being subject to any resulting detriment, withdraw the minor from the trial at any time by revoking the informed consent.

In the event of an emergency the above points do not apply

• The minor has received information, according to his or her capacity of understanding, about the trial and its risks and benefits.  The information must be given by staff with experience with minors.
• The investigator must consider the explicit wish of a minor capable of forming an opinion and assessing the information provided. This applies both to the wish of a minor to refuse to take part, or to withdraw from the trial at any time.
• No incentives or financial inducements are given either to the minor or to the parent or legal representative, except the provision of compensation for injury or loss.
• The clinical trial relates directly to a condition from which the minor suffers or is of such a nature that it can only be carried out on minors.
• Some direct benefit for the group of participants involved in the trial is to be obtained from the trial.
• The trial is necessary to validate data obtained (a) in other clinical trials involving persons able to give informed consent, or (b) by other research methods.
• The corresponding scientific guidelines or the European Medicines Agency (EMEA) are followed.

Principles

• Informed consent by a parent or legal representative shall represent the minor’s presumed will.
• The trial has been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the minor’s stage of development.
• The risk threshold and the degree of distress have to be specially defined and constantly monitored.
• The interest of the participant always prevails over those of science and society.

It is vital that all participants who are recruited into a clinical trial, sign consent before any trial related procedures occur.

In line with GCP and ICH guidelines, the participants must be given a patient information sheet detailing the study which must be introduced and discussed with a GCP qualified person, usually the doctor in charge of the participant or a research nurse. This must also include informing the participant of any pain implications or about possible risks or side effects as well as discussing any possible alternative treatment. The participant must have ample time to consider the study and should be advised to talk it through with members of their family.  Once they have had time to answer any questions then with the GCP delegated person the consent form can be signed.

The original consent form must be filed in the Investigator Site File together with a copy of the patient information sheet in recruitment order, with a copy for the participant and a copy in the participant’s medical records.

This process needs to be clearly documented in the medical records including the full study title (avoiding the sole use of acronyms).

• Voluntary agreement to participate in the clinical trial
• Refusing to participate or discontinuation will have no penalty
• A clear box with patients allocated trial number
• The possible consequences of withdrawal
• Acknowledgement of the information that has been provided and all patient’s questions have been answered
• A clear guidance of patient confidentiality and data collection
• The patient’s legal representative agreement that the sponsor’s representatives, regulatory authorities and REC will be given access to the patient medical records
• In line with the Human Tissue Act, details of any tissue taken will be anonymised and stored appropriately.

In cases where the participant is unable to read or write or speaks another language, then a witness should be available to ensure that the participant has been informed and has had time to consider the study and ask questions.  As well as the participant or the legal representative the witness should also sign and date the consent form to confirm that the information was accurately explained and that the informed consent was given.

The Site Initiation Visit (SIV) is required to prepare and set up a research site to conduct a study and must occur prior to patient recruitment. 

The principal investigator (PI) must attend this visit together with as many members of the research team as possible. Representatives from any supporting departments should also attend where possible e.g. pharmacy, radiology, laboratories.

If NBT have agreed to sponsor your study, they are required to attend the SIV. Please provide the Research & Innovation Office advance notice of the date for the SIV to ensure attendance.

The role of this meeting is to discuss the protocol, especially the inclusion/exclusion criteria, study procedures, and the research participant pathway the sponsor will discuss the monitoring plan for the study – including safety reporting procedures and monitoring to Good Clinical Practice (GCP) and International Conference on Harmonisation (ICH) requirements.

When conducting the site initiation visit (SIV):

• Review the protocol in detail
• Review instruction on any specialised procedures such as diagnostic tests and special computer programs
• Receive direction for Case Report Form (CRF)/electronic CRF completion & safety reporting
• Define source documents
• Be prepared to provide sponsor with an update on any study related
• Issues
• Document all study related training
• Review the Investigator Site File 

All documentation generated before, during and after undertaking a research project must be kept together in an Investigator Site File. It is important that such documentation is complete, legible and easily accessible at any time for monitoring and or audit purposes.

For every research study it is important to keep clear accurate version controls of all trial related documents including; Protocol, Patient Information Sheet (PIS), consent, GP letter, trial specific procedures and Standard Operating Procedures (SOPs). The current approved versions of all study documents must be filed in the Investigator Site File. All previous versions must also be retained in the Investigator Site File clearly marked as superseded (with details of current approved version number and date, initialled and dated.

The study documentation also serves some other important purposes:

• To demonstrate the compliance of the investigator, sponsor and monitor in accordance with Good Clinical Practice (GCP)and International Conference on Harmonisation (ICH) guidelines and any regulatory requirements
• Assist all parties in the successful and smooth management of the research;
• Provide monitors/auditors with the necessary information they need to confirm the validity of the research, its conduct and the integrity of the data collected

If NBT is the sponsor, then we can provide the Investigator Site File and index pages. To request this, please contact us via research@nbt.nhs.uk.

If you are the Lead Site of a multi-centre study, sponsored by NBT, we will also provide you with Master Trial Files with index pages – it will be important to clearly label the volumes of these files with appropriate indexes.  These files will contain all documentation relating to the research study and to all the recruitment sites involved in the conduct of the study. As a Lead Site, you must provide an Investigator Site File for each recruiting site.

The Investigator Site File will contain only documentation relating to the local recruiting site i.e. participant consent forms (which should be protected by envelopes to maintain confidentiality) and local screening and recruitment logs. Where you are a Lead Site and a recruiting site, there may be duplication of some documents, but this is required to maintain a clear documentation trail for monitoring and audit purposes. In this situation, please note that the duties on the local delegation log may differ from that on the delegation log in the Master Trial Files.

In line with GCP & ICH guidelines, the Investigator Site File and Master Trial Files (where applicable) must be kept in a secure locked room as some of the contents will contain patient related data and must be kept confidential.