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:

- 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 well being 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/amendments 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 the 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 Competent Authority (MHRA), Ethics Committee and other Principal Investigators according to Article 16(4) and Article 17 (1a, b and d) of the Clinical Trials Directive. 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 and REC. The reporting timelines are based on two factors:

- If life threatening, within 7 days of the becoming aware of the reaction

- If non-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. Download the pdf copy of the submitted report and submit this to REC using the CTIMPs Safety Report form online.

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, in writing, of the measures taken and the reason for the measures within three days.

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

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

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.

The REC, MHRA (as applicable) and relevant R&D department must approve substantial amendments, before they are implemented (Where a project has HRA Approval and has been reviewed by a REC, the substantial amendment only needs to be reviewed by REC). Some substantial amendments only require authorisation by the REC, such amendments do not have to be notified to the MHRA. Where the substantial amendment requires authorisation by the MHRA and the REC, submission to both bodies is still required.

MHRA do not need to be notified of non-substantial amendment but the sponsor should be notified including when it was implemented, and records should be kept in the Trial Master File. Other (non-substantial) amendments: Where the lead NHS R&D office is in England you should submit the amendment to hra.amendments@nhs.net 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 will review all the amendment documents before you submit to Ethics and MHRA.

For projects which are approved via Combined Review Service, the amendment 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 amendment using the notification of amendment form 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 amendment using the notification of amendment form 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 available from the MHRA website and including a brief explanation of the reasons for ending the trial.

All CTIMP projects require annual reporting. There are two types of reports submitted to REC and MHRA on the anniversary of receiving approval.

- DSUR (submitted to MHRA and REC)

- APR (submitted to REC)

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 all CTIMP studies that received approval after Jan 2022, should be done via Combined Review Service.

The annual progress report (APR) should be submitted to REC only. This should be submitted within 30 days of the REC favourable opinion anniversary. The template of the APR should be obtained from HRA website.

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 substantial amendment. In most cases, it 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 (The completed form must be submitted to both MHRA and REC).

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. The Chief or Principal Investigator and/or the Sponsor are also responsible for uploading the end of trial summary results to ISRCTN/EudraCT/Clinicaltrial.gov as per the commission’s guidelines on posting and publication of result-related information. 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’ as the subject line.

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