Trial management

Sponsorship & set-up

Sponsorship

All research projects require a sponsor and BWC can sponsor most research projects. The sponsor takes responsibility for all aspects of the trial. Sponsor responsibilities may be shared with other Organisations (co-Sponsors) and it is expected that in making the Sponsor decision for the Organisation all Sponsor responsibilities are clearly documented and attributed. Wherever possible the NIHR Model template agreements should be used.

Following the decision to Sponsor a Study, the Sponsor Organisation is responsible for continued oversight of its involvement in the conduct of the project including provision for all monitoring arrangements whether they are conducted by the Sponsor or Participating Organisation.

If you are planning to carry out any research project, that currently doesn’t have a sponsor in place, please contact the R&D office and our team can look into this for you.

It is advised that when requesting sponsorship, a copy of your draft proposal, details of any funding and any other information about the project is submitted to R&D so that a risk assessment can be performed. The risk assessment identifies risks relating to your project and all procedures to be undertaken. The R&D office will complete the risk assessment with assistance of the Chief Investigator when necessary.  In considering to undertake the role of sponsor the department will use the Sponsoring Organisation Assessment tool, which allows quick identification of risks and actions needed to comply with sponsorship responsibilities.

It considers 10 key aspects:

  • Chief investigator
  • Resources
  • Trial design and sites
  • Complexity of Trial
  • Recruitment
  • Trial and Data Management.
  • IMP/intervention information
  • Conflict of interest.
  • Feasibility
  • Finance

Once the risk assessment is complete, it will be discussed at the Sponsorship Oversight Group. Dependant on the risk outcome will depend upon the level of detail that will be discussed at the meeting. If the project is deemed high risk, the Chief Investigator or delegate will be invited to the meeting to discuss their project in more detail.

In order for Birmingham Women’s and Children’s NHS Foundation Trust to consider acting as sponsor for a research project the following must be considered:

  1. The Chief investigator must have a substantive employment contract with the Trust. Where the CI does not hold a substantive employment contract with the Trust, they must have at least an Honorary Contract and all other avenues of sponsorship by the substantive employer exhausted. Where honorary contract status applies, this will require automatic referral to Sponsorship Oversight Group for all Clinical Trials for review.
  2. Chief investigator must have completed GCP training (within last 2 years), and have a proven track record in delivering Research projects.
  3. BWCH will consider sponsorship of Clinical Trials of investigational Medicinal Products for phases I or II as part of the Clinical Research Facility on a case by case basis.
  4. Sponsorship for Multi-Centre Clinical Trials will automatically referred to Sponsorship oversight Group.

Sponsorship in principle will be issued if it has been agreed that BWC can sponsor your project and R&D will proceed with any further sign offs.

Once the project has received all of the necessary approvals, such as REC, MHRA (if required) and HRA then BWC R&D will issue a final sponsorship letter along with final R&D confirmation.

For more information on sponsorship, please contact the R&D office.

Set-Up

The sponsor will submit the REC/HRA application pack for review and will provide advance warning of the protocol and other supporting documents e.g. laboratory/pharmacy/imaging manual, Schedule of Events Cost Attribution Tool Contract (Non-commercial) or NIHR Costing Template/Contract (Commercial) to the local R&D office as soon as possible prior to receiving regulatory Confirmation of Capacity and Capability s so that a provisional assessment can be made.

The R&D office will add projects to our local database and review documentation and any other supporting documentation received to understand local requirements. R&D will contact the local PI to undertake a provisional assessment. The PI will have 10 working days to provide a response. If no response or the PI does not wish to participate, R&D will inform the sponsor.

If the PI is happy to be involved, R&D will start the Assess Arrange and Confirm process and request any further documentation required from the sponsor. During the AAC process, the Facilitation team have regular review meetings to determine priority of projects currently in set up. 

Prior to any contracts signed and AAC letters sent, the project undergoes a final quality check to ensure everything is in place before final approval is given. Once this has been internally signed off, R&D will formally sign any contracts between us and the sponsor/funder and issue the AAC letter confirming our capacity and capability to run the project at this site. R&D uses the local database to record this information.

The internal database is updated with relevant information, including the date we opened to recruitment.

There are other projects that don’t need an assessment of Capacity and Capability and/or if BWC are a PIC, Patient Identification Centre and/or BWC are a Continuing Care Site.

For more information, please contact the R&D office

IRAS

IRAS logo The Integrated Research Application System (IRAS) is a single system for applying for the permissions and approvals for health and social care / community care research in the UK.

IRAS captures the information needed to submit for relevant approvals for the following review bodies:

  • Administration of Radioactive Substances Advisory Committee (ARSAC)
  • Gene Therapy Advisory Committee (GTAC)
  • Medicines and Healthcare products Regulatory Agency (MHRA) – Medicines and Devices
  • Ministry of Justice (National Offender Management Service)
  • NHS / HSC research offices
  • NRES/ NHS / HSC Research Ethics Committees
  • Patient Information Advisory Group (PIAG)

The IRAS system is designed for UK-wide use.

IRAS consists of a single integrated dataset:

  • This is the set of questions and answers for all the questions in all the application forms.
  • The set of questions that need to be answered by a researcher will depend on the type of study and the types of applications required

The application forms for each reviewing body are generated from the single dataset – i.e. information about the project in response to a question is entered only once.

The single dataset and application forms cross-populate

 In IRAS, once you have completed one form you will find that other forms will already contain all the duplicated information you have completed elsewhere.

An online module has been added to the IRAS website to guide new users through IRAS. The module explains how IRAS is structured and guides users through how to prepare and make applications using IRAS: https://www.myresearchproject.org.uk/elearning/

Local document package

Once the sponsor receives the HRA Approval initial assessment letter (or HRA Approval letter in cases where no initial assessment letter is issued) they can contact participating NHS sites in England to provide them with the 'local information pack' and finalise discussions around confirming capacity and capability. 

Once all the arrangements have been put in place to deliver a study, the participating NHS organisation will provide you with confirmation of this via email, indicating that they are ready to start the study. The actual date at which you wish to start research activities at the site should have already been agreed and may be dependent on a site initiation visit or similar that you wish to conduct.

The local information pack should contain;

  • Copy of IRAS Form as submitted Protocol and amendments
  • Participant information and consent documents (without local logos/ headers)
  • Relevant model agreement
  • Localised Organisational Information Delegation log (where applicable, including known research team names but not signatures, or      indicate when this will be shared)
  • Commercial studies only – NIHR Costing template (validated)
  • Non-commercial studies only - Schedule of Event or Schedule of Event Cost Attribution Tool
  • Any other documents that the sponsor wishes to provide to the site to support the set up and delivery of the study
  • Copy of Initial assessment letter (if one is issued) and (when issued) HRA Approval letter and final documents.

The HRA initial assessment or HRA Approval letter will provide information relevant to study set up. Any cost negotiations that are required with the participating organisation can be finalised at this stage.

For more information please visit the HRA website; https://www.hra.nhs.uk

Amendments

According to HRA, amendments are changes made to a research project after approval from a review body has been given. If any amendments are planned to take place, you will need to determine whether you need to notify the review bodies from whom you received original approval. (REC, MHRA and HRA)

There are two classifications for amendments; substantial and non-substantial. Regardless of classification all amendments must be reviewed, agreed and authorised by the sponsor and CI. Amendments to research projects are classified into 2 types:  Substantial and Non-substantial.

Substantial amendment is defined as an amendment that is likely to affect to a significant degree any of the following:

  • The safety or physical or mental integrity of the participants of a research project.
  • The scientific value of research project
  • The conduct or management of the research project
  • The quality or safety of the Investigation Medicinal Product

Non-substantial amendments are minor changes that are not considered substantial as described above and can include, but not limited to:

  • Minor changes to the protocol or other documentation; correcting errors etc
  • Investigator brochure update
  • Extending the project beyond specified end date in original application.
  • Changes to research team at particular site
  • Changes to funding arrangements. 

 

Ultimately, it is the sponsor’s decision whether an amendment is substantial or non-substantial.  Substantial amendments that require REC review are submitted by email to the REC that originally reviewed the research project and then reviewed by HRA.  Non-substantial amendments or any amendments that do not require REC review should be submitted to the HRA. 

Regulatory approvals must be in place before any amendment can be 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 amendments, but BWC as sponsor should be notified including implementation date and all records should be made and kept in the Trial Master File.

For Study wide approvals of studies being processed through the HRA please refer to guidance set out on the HRA website for the UK Process for Management of Amendments.  Click on link for further information : http://www.hra.nhs.uk/nhshsc-rd-uk-process-management-amendments/

For more information, please contact the R&D office

Pharmacovigilance and Safety reporting

To comply with The Medicines for Human Use (Clinical Trials) Regulations 2004 and International Conference on Harmonisation Guidelines for Good Clinical Practice it is important that all researchers are aware of the different definitions of Adverse Events (AE’s) in research and how to record, report and review each of these specific occurrences. All AEs that occur during the course of a research project must be recorded and reported appropriately in order to ensure that the patient safety is maintained.

The Medicines for Human Use (Clinical Trials) Regulations 2004 apply to adverse event reporting requirements for all Clinical Trials of Investigational Medicinal Products (CTIMPs); non-CTIMP research projects also have specific adverse reporting requirements whilst they do not fall under the same regulations they fall within the guidance of the Research Governance Framework 2005 for all research conducted within the NHS setting. Failure to comply with AE reporting requirements constitutes a serious breach and can result in the withdrawal of approval of the research, or, in significant cases, prohibition of research conducted by an individual investigator or an organisation.

Where AEs are reported, it is the responsibility of the Chief Investigator to inform the Sponsor and PIs at participating sites of any relevant information that may affect patient safety.

Where Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported, it is the responsibility of the Chief Investigator to inform the Sponsor and PIs at participating sites of any relevant information that may affect patient safety.

It is the CIs responsibility to review Serious Adverse Events (SAEs) submitted by participating sites and reviewing causality. The CI has the ability to upgrade or downgrade reported events, however must inform the site and the Sponsor of any decisions.

Copies of all SAEs for studies where BWC sponsor the study should be sent to bwc.research-qualityandsafety@nhs.net. The form should be fully completed and signed by the PI or appropriate delegate and should be reported within the specified timeframe given in the study protocol.

For more information, please contact the R&D office

Temporary Halt / Early closure

It is essential R&D is informed if any halt to a trial is agreed. The MHRA (if required) and REC should be notified immediately, at least 15 days from when the project was temporarily halted. This should be raised as a substantial amendment and clearly explain what has been halted and the reason for this decision.

To restart a project that has been temporarily halted, another amendment should be submitted detailing the evidence it is safe to reopen the project.

If it has been agreed that a project will be terminated early or will not be restarted, the end of trial notification must be completed, detailing an explanation of why this decision was made and submitted within 15 days of this decision to MHRA and REC.

Please keep R&D informed of any decisions made to the project, especially where BWC act as sponsor for your project.

Where a study is temporarily halted, the CI or delegated person must inform the REC that provided the Favourable Opinion and/or MHRA (for CTIMPs), in the form of a substantial amendment and clearly explain what has been halted and the reason for this decision, immediately or within 15 days from when the trial was temporarily halted, the R&D Office should be copied in to this correspondence. The reasons for the temporary halt should be clear, and should be reported to the R&D Office. When the study is able to re-start, the CI/ delegate retain the responsibility for submitting a substantial amendment. The CI or delegate should ensure that a copy of the Declaration of the end of trial, as supplied to the REC/ MHRA is also sent to the R&D Office via email. This should also include acknowledgement of receipt. A copy of both the End of Trial acknowledgement and receipt should be filed in the TMF.

Serious breaches

A “serious breach” is a breach which is likely to effect to a significant degree:

(a) The safety or physical or mental integrity of the participants of the trial (this should be relevant to trial participants in the UK); or

(b) The scientific value of the trial.

The judgment on whether a breach is likely to have a significant impact on the scientific value of the trial, depends on a variety of factors e.g. the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the data from the analysis etc.

When a serious breach occurs the CI must complete a serious breaches notification form and submit to the relevant regulatory authority;

MHRA; GCP-PV.Inspectors@mhra.gsi.gov.uk

HTA; https://www.hta.gov.uk/make_an_enquiry?nature=367

REC; HRA.Queries@nhs.net

HFEA; enquiriesteam@hfea.gov.uk

The CI must send a copy of the Serious Breach notification form to the R&D office bwc.research@nhs.net 

All Serious Breaches will be reviewed at the Sponsorship Oversight Group meetings; however the Chair of the SOG group will be informed along with the relevant Executive Lead for R&D at the time of occurrence.

All Serious Breach reports will be disseminated to the Trust Board when requested, as well as the RSIC.

For more information, please contact the R&D office

Urgent safety measures

Urgent safety measures are there to be actioned to protect participants from immediate harm to their health and safety. These should be triggered immediately and do not need to wait for any authority approvals before implementation.

The Chief Investigator should phone the Clinical Trial Unit at MHRA and discuss the issue with a safety scientist immediately. The MHRA and REC must be notified in writing within three days. A substantial amendment should be submitted in order to include any changes made as a result of the safety measure. 

Trial End/Archiving

The definition of end-of-project should be defined in the protocol and any change to this should be submitted via a substantial amendment. In the majority of cases, it will be the last visit of participant or completion of any follow-up/data collection. 

The protocol determines:

a) The date for the conclusion of the study.

b) The event which indicates that the end of the study has occurred.

Some studies terminate prior to the conclusion date or event because of:

a) Safety concerns.

b) Poor toleration of the study intervention (patient-related reaction).

c) Slow recruitment.

d) Sponsor’s decision.

e) Investigator’s decision.

f) Regulatory decision (e.g. MHRA).

It is the responsibility of the Principal Investigator (PI) to inform the Chief Investigator (CI) that the study at that site is terminated. Where BWCH are the Sponsor for the study, the CI must inform the R&D Office by email when a site has terminated its participation in the study. In order to support accurate overview and reporting of research activity in the Organisation, a study closure tracking and study end dates will be recorded in the appropriate R&D Database.

For a study which is terminated early for reasons other than full recruitment being reached, the CI or delegated person must notify the REC which provided Favourable Opinion and/ or the MHRA immediately and no later than 15 days after the research has been halted, the R&D Office should be copied in to this correspondence. The CI/ delegate is advised to use the current guidance on the regulatory body’s website. The reasons for the early termination should be clearly explained along with all follow-up measures, where appropriate, for safety reasons. Where studies have been terminated early or suspended, the R&D Office must be informed immediately. The Sponsor of a study has an obligation under ICH GCP Guidelines and EU Regulations to ensure that research project documentation is appropriately stored and retained for a defined period following completion of a research project. Archiving is necessary to enable the evaluation of study conduct.

The Trust is expected to archive the Essential Documents (which individually and collectively permit evaluation of the conduct of studies and the quality of the data). Essential documents should be stored in a way that allows accurate reporting, interpretation and verification. This should be done by the PI and/or Trust as agreed. It is the responsibility of the Sponsor to retain Sponsor specific Essential Documents.

The research study records are expected to be sent to the appropriate records centre (securing the long term storage) at the end of the study by the R&D office as agreed. This is to comply with the Research Governance Framework 2005, the Data Protection Act 1998 and the NHS Organisation’s policy on the retention and disposal of records (based on the Department of Health recommendations on record retention). Page 5 of 19

The research study agreement will formally document who is responsible for archiving Essential Documents. When the Sponsor undertakes this responsibility they will work according to their policy. It remains the Sponsor’s responsibility to determine when the research project documentation can be put for destruction.

In some cases, the Sponsor or member of the research team may wish to review the research projects documentation that are in archive. Permission must be sought from the R&D Office to recover the items from archive by completing the Archiving Retrieval Form Any requests should be made to the R&D Archivist. This can be completed by any member of the research team, however, must be signed off by the CI/ PI. Any requests that relate to an inspection or audit should be marked ‘URGENT’.

For more information, please contact the R&D office

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