Clinical Trials

A protocol is defined as “a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial”. The term protocol also refers to, successive versions of the protocol and protocol amendments. The clinical trial protocol should meet a specific standard according to ICH Good Clinical Practice (GCP) guidelines. Please refer to the Protocol Template and forms subsection of this page which can be adapted for your Clinical Trial Protocol development. The Clinical Trials Team will provide support and advice to ensure your clinical trial protocol is Good Clinical Practice compliant. This is required before GOSH Sponsorship can be confirmed.

For CTIMPs, where GOSH is asked to act as the Sponsor or co-sponsor, the Clinical Trials Team will assist in the completion of the risk assessment working with the Chief Investigator and the trial team as necessary. A CTIMP risk assessment can be completed using the risk assessment form which includes identifying risks related to protocol and its procedures and mitigating them.

To be considered for GOSH sponsorship for any project, the CI must have been involved in the development of the protocol and must be a GOSH substantive employee or honorary employee.

The minimum following documentation should be provided to the Clinical Trials Manager before sponsorship of CTIMPs can be assessed:

- Draft/final protocol or trial proposal

- Details of trial funding

- Details of drug supply

We have an expert advisory panel to review CTIMP studies and consider Sponsorship by GOSH. Once a protocol has been agreed and a risk assessment has been completed, the Clinical Trials Team will arrange for your study to be reviewed by the Sponsorship Panel to discuss the risk elements. If the trial has high risk elements, individuals from the trial team may be invited to the meeting to present the trial in a format defined by the Panel or clarify the queries via email.

Once all queries are resolved and risk assessment is fully signed, the sponsorship panel will confirm sponsorship via an approval letter.

Once the sponsorship is confirmed, the study team should plan to submit the application to MHRA and REC. To make this application you will need the following documents at minimum:

• Covering letter
• Protocol
• Investigator Brochure or SmPC, if licenced product
• Investigational Medicinal Product Dossier
• Patient Information Sheets, Consent Forms and Assent Forms
• GP letter
• IRAS form
• Insurance letter (provided by Clinical Trial Team)
• Any other related document as required per your trial

The documents should be reviewed and approved by the R&D clinical trial team.

The study team should complete the IRAS form using Combined Review Service (CRS) on IRAS to submit an application to MHRA and REC. You will need an IRAS account to submit the application.

Once all approvals are in place, the study team should liaise with R&D clinical trial team to initiate the project.

The study will be reviewed by a Governance Officer and/or the Clinical Trial Team to check the capacity and capability within R&D and across different departments involved in the conduct of the study. The investigator/study team must liaise with each department involved in the study to obtain their capacity and costings associated with each procedure conducted during the study. A final Chief of Service confirmation of capacity and capability is required following receiving confirmation from all other contributing departments.

Monitoring is a requirement of the Good Clinical Practice Directive and the UK Policy framework for Health and Social Care research. This is a responsibility of the Sponsor and ensures that there is oversight of the study conduct. The purpose of monitoring is to verify:

- The rights and wellbeing of human subjects are protected

- The trial data are accurate, complete, and verifiable from source documents

- The conduct of the trial is compliant with the approved protocol/modifications and with the applicable regulatory requirements.

The Site initiation visit takes places prior to the start of the study. Its purpose is to ensure the site is prepared for the enrolment of participants, that all staff are trained on the protocol requirements and understand their role in the study. The protocol, study procedures, data collection, pharmacovigilance, Good Clinical Practice and reporting requirements are discussed with the Chief Investigator/s, Principal Investigator/s, research team and staff from all relevant departments present.

Following the Site Initiation Visit, the Sponsor will request records to verify that all regulatory approvals, contracts, confirmation of capacity, and necessary documentation are in place. This process is referred to as the ‘regulatory green light’. Once this has been confirmed, the trial can be authorised to begin and research sites can be given the ‘green light’ for participant recruitment start.

Monitoring is an ongoing process until the completion of the trial. Following the Site Initiation Visit, there will also be:

- Interim Monitoring Visits

- Close-out visit

A monitoring plan will be created, in line with the risks associated with the study, and will detail the frequency and requirements of the visits. Monitoring of the study will include verification of source data, regulatory filing, IMP accountability, pharmacovigilance, non-compliances and breaches.

The GOSH/UCL GOS ICH R&D office is responsible for keeping detailed records of all serious adverse events/reactions in clinical trials of investigational medicinal products where GOSH is the Sponsor or host organisation. For GOSH sponsored studies, the R&D office is responsible for reporting SUSARs to the MHRA under regulations 33 and 34 of the Clinical Trials Regulations, including those that:

• are associated with comparators and placebos (where an SAE is related to placebo)
• occur at non-UK sites if there are also trial locations in the UK
• occurred during the trial but were identified after trial completion.

For externally sponsored studies, GOSH has a responsibility for patient’s safety as the hosting organisation.

All SAEs/SUSARs from GOSH sponsored and externally sponsored studies (where GOSH is a site) shall be reported to GOSH/ICH R&D Office within 24 hours of the notification of the event or within the timeframes specified for SAEs and SARs in your CTIMP protocol. Please refer to the Pharmacovigilance and Safety Reporting SOP (GOSH/ICH/SOP/R&D/007) and GOSH/ICH/SOP/R/005 in standard operating procedures and templates subsection on this page.

The R&D Department has a template Serious Adverse Events Reporting Form which you can use to report SAEs/SUSARs or Form 20 for any other important safety issues during the study conduct (both can be found under standard operating procedures and templates subsection), you will need to email a copy of the signed form to the team.

All SUSARs must be submitted to the MHRA. The reporting timelines are based on two factors:

- If fatal, within 7 days of the becoming aware of the reaction

- If life threatening, within 15 days of becoming aware of the reaction

To begin the SUSAR reporting process, the reporter must complete a report for the SUSAR on the MHRA ICSR portal. You will need a log-in details to complete the form. Request this from the R&D Clinical Trial Team. Once the report is fully completed it is then reviewed by both CI and R&D office before it is ready to submit via the MHRA ICSR portal.

You may take appropriate urgent safety measures to protect clinical trial subjects from any immediate hazard to their health and safety. The measures should be taken immediately. You do not need to wait for Licensing Authority approval before implementing urgent safety measures.

The Chief Investigator should phone the Clinical Trials Unit at the MHRA and discuss the issue with a safety scientist immediately. The Chief Investigator should also inform the Clinical Trials Manager immediately and Trials Manager will notify the MHRA and the Ethics Committee of the measures taken and the reason for the measures within seven days.

If the trial was approved through the combined review process, this will be notified via IRAS.

For trials that were approved through separate applications to the licensing authority and ethics, an email will be sent to the licensing authority (clinicaltrialhelpline@mhra.gov.uk).

A substantial modification should be submitted subsequently to incorporate the changes made to the protocol or any other documents.

All modifications must be notified to the sponsor for review prior to submission.

A substantial modification is defined as an modification to the terms of the protocol or any other supporting documentation that is likely to affect to a significant degree.

Modifications can be:

• Route A Substantial Modification which significantly impact participant safety or scientific value of the trial.
• Route B Substantial Modifications are lower risk changes which do not alter safety or scientific integrity.

Non-Substantial Modifications are split into 2 categories: Modifications of an Important Detail (MOID) which are changes notified to the authorities for oversight, or, minor modifications which are administrative changes not required to be submitted for review.

Refer to this link for examples of modifications: Examples of modification types - Health Research Authority

The REC, MHRA (as applicable) and relevant R&D department must approve substantial modifications, before they are implemented (where a project has HRA Approval and has been reviewed by a REC, the substantial modification only needs to be reviewed by REC). Route A Substantial Modifications require full review (MHRA, HRA and REC); Route B Substantial Modifications do not require full review as these do not introduce significant safety concerns, they are instead subject to a risk-proportionate review instead of a full assessment. Non-Substantial Modifications do not require REC or MHRA review, but HRA and HCRW approval may be required.

MHRA do not need to be notified of non-substantial modifications but the sponsor should be notified including when it was implemented, and records should be kept in the Trial Master File. Other (non-substantial) modifications: Where the lead NHS R&D office is in England you should submit the modification to amendments@hra.nhs.uk and for studies where the lead NHS R&D office is in Northern Ireland, Scotland or Wales the categorisation will be undertaken by the lead nation. Please refer to the Amendments SOP(GOSH/ICH/SOP/R&D/005) in the standard operating procedures subsection. The Clinical Trials Manager/Clinical Trials Coordinator will review all the modification documents before you submit to Ethics and MHRA.

For projects which are approved via Combined Review Service, the modification should be submitted via Combined Review Service, otherwise it can be submitted by email to the REC who provided the initial approval for the study and via the MHRA submission portal.

Please inform R&D promptly if you decide to halt a trial temporarily. The MHRA and Ethics Committee should be notified immediately and at least within 15 days from when the trial is temporarily halted. The Trials Manager will assist you in the notification that should be made as a substantial modification and clearly explain what has been halted (e.g. stopping recruitment and/or interrupting treatment of subjects already included) and the reasons for the temporary halt.

To restart a trial that has been temporarily halted, the Trials Manager will assist you to request the reopening as a substantial modification and providing evidence that it is safe to restart the trial.

If you decide not to recommence a temporarily halted trial or decide to terminate a trial before the date specified for its conclusion please inform R&D at the earliest as MHRA and Ethics Committees should be notified within 15 days of this decision, using the End of Trial Declaration form on IRAS.

All CTIMP projects require Development Safety Update Reports (DSUR) annually.

The Development Safety Update Report (DSUR) must be submitted to MHRA and REC following the annual reporting SOP. The first DSUR may be submitted after one year of the Developmental International Birth Date (DIBD) for the drug, this is usually the first clinical trial authorisation (CTA) received. The DSUR should be submitted no later than 60 calendar days from the data lock point. The DSUR template can be obtained from R&D Clinical Trials Team.

It is to note that DSUR submission for all CTIMP studies that received approval after Jan 2022, should be done via Combined Review Service.

The definition of the end of the study should be clearly defined in the protocol and any change to this definition should be notified as a modification of an important detail (MOID). In most cases, end of trial will be the date of the last visit of the last participant or the completion of any follow-up monitoring and data collection described in the protocol.

Final analysis of the data (following ‘lock’ of the study database) and report writing is normally considered to occur after formal declaration of the end of the study.

The Clinical Trials Team should be notified promptly of the trial completion and the Trials Manager will notify the MHRA and Main REC within 90 days of the end of the Clinical Trial by completing the End of Trial Form on IRAS.

The publication policy of a Clinical Trial should be addressed in the protocol. The Chief Investigator should provide a summary of the Clinical Trial Report to the Clinical Trials Team, within one year or 6 months if a paediatric study, following the submission of the end of the trial declaration. This will be submitted to the main REC and MHRA via IRAS. The Chief or Principal Investigator and/or the Sponsor are also responsible for uploading the end of trial summary results to where the clinical trial is registered (ISRCTN/EudraCT/Clinicaltrial.gov). You don’t need to submit this clinical trial summary report to the MHRA as well. However, you must send a short confirmatory email to CT.Submission@mhra.gov.uk once the result-related information has been uploaded to EudraCT, with ‘End of trial : result-related information: EudraCT XXXX-XXXXXX-XX’ and/or IRAS ID XXXXXXX’ as the subject line.

More information on conduct of CTIMPs can be found on the HRA andMHRA GOV UK websites.