Planning a Clinical Trial
The following section will provide guidance to Cardiff University employees in setting up Clinical Trials covered by the Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments (hereafter referred to as "the Regulations"). These regulations implement the EU Clinical Trials Directive in the UK. To help you decide whether your proposed project is a Clinical Trial under the Regulations please refer to 'Is my study a 'Clinical Trial?'
The Clinical Trials Toolkit website is also a useful resource, including interactive “route maps” to help guide researchers through trial management processes.
Planning a Clinical Trial - What needs to be done?
- Protocol Development
- Trial Master File
- Partner Consultation
- Risk Assessment
- Apply for Funding
- Develop Trial Documnentation
- Finalise Contracts
- EudraCT Number
The first step in setting up a Clinical Trial is to develop an outline protocol to describe the basic details of the trial. The outline protocol may then be used when discussing the trial with potential trial partners and the study Sponsor. A Clinical Trial protocol should be written according to Good Clinical Practice (GCP) standards. For guidance please refer to: SOP Protocol content and format to meet ICH-GCP standards
It is a statutory requirement that all clinical trials that fall under the Medicines for Human Use (Clinical Trials) Regulations 2004 have a named Sponsor. The Sponsor must satisfy itself that the study meets all relevant standards and ensures that arrangements are put and kept in place for adequate management, monitoring and reporting.
It is important to identify a Sponsor as early as possible. Many funding bodies require a Sponsor in principle to be agreed prior to funding application. First establish whether an external partner (e.g. funding body, NHS Trust, Clinical Trials Unit) is willing to take on the role of Sponsor. If you wish Cardiff University to act as Sponsor, you should contact the Research Governance Team. Confirmation that Cardiff University will accept Sponsorship can only be given in writing by RACD on behalf of the University. Guidance on the procedures for obtaining Sponsorship from Cardiff University is provided in the SOP-Obtaining Acceptance of Sponsorship from Cardiff University (CTIMPs). A Sponsor Registration form is available here
You should also start preliminary discussions with the Contracts Team at this stage to discuss potential contract requirements.
A Trial Master File should be set up at the beginning of a trial. Notes of all discussions and key documents should be retained in a Trial Master File (TMF). To set up a TMF, please refer to:
The TMF and Trial Subject File must be stored in an appropriate and secure central location. Cardiff University’s Governance and Compliance Division can provide further information on archiving, record management and Off Site Storage Arrangements.
Once a research idea has been developed, you should liaise with potential trial partners.
Discussing the trial with potential partners will ensure that potential issues are identified at an early stage. Please note that where confidential information may be exchanged with a potential trial partner, a confidentiality agreement should be in place prior to discussing the trial in detail with that potential partner. To set up a confidentiality agreement, please contact the Contracts Team in RACD.
Once initial discussions are complete, you will need to formalise relationships via a contract. Contracts may only be signed by authorised signatories at the University. The RACD Contracts Team should be involved in all contract negotiations.
Areas which you should consider include:
Do the Trial team have sufficient experience?
- Check that they have up to date Good Clinical Practice training and evidence of such training
- Check CVs to determine if they have prior experience of Clinical Trials
Will external funding be secured?
- Identify if there are funding opportunities available
Have trial management arrangements been considered?
- Will a Clinical Trials Unit be involved?
- Consult a medical statistician. A medical statistician will need to approve the design and methodology and also carry out the statistical analysis. The following EMA documents are essential reading : E3 - Structure and Content of Clinical Study Reports, E9 - Statistical Principles for Clinical Trials & CFPMP - Committee for Proprietary Medicinal Products.
- How will pharmacovigilance responsibilities be met?
Will host organisations be able to support the trial?
- Contact host organisations (e.g. NHS Trust R&D Offices) to check they have resources and facilities available and that they wish to support the trial
How will the Investigational Medicinal Product (IMP) be managed?
- Identify whether the IMP has license and whether it is available in the form you require
- Consider whether a pharmaceutical company can supply the IMP
- Determine who would be responsible for IMP preparation, accountability and distribution. In the first instance discuss with the Clinical Trial Pharmacist at the lead NHS Trust
For each clinical trial a risk assessment should generally be undertaken at the protocol development stage. This may be used to plan the details of trial management and the approach to, and extent of, monitoring in the trial. These plans should be documented, together with the risk assessment, so that the management strategy is both transparent and justified. This documentation is intended not only to facilitate the management of the trial but also to help prepare for external audit. Please refer to Cardiff University's Risk Assessment Form and Risk Management Strategies document.
For each clinical trial an IT Survey must be completed to ensure planned IT systems are appropriate.
Once Sponsorship has been accepted in principle, the CI can apply for funding following the normal Cardiff University costing process. For further information regarding this process please contact the RACD Pre-Awards Team.
Whilst completing the costing process ensure the following costs have been considered:
- Trial management costs - have you costed time for trial statistician, managing product accountability, adverse event reporting, trial management, trial monitoring, data management and archiving etc?
- NHS excess treatment and Service support costs
- IMP management
- University Clinical Insurance
- MHRA Clinical Trial Authorisation
- Time and costs for fulfilling regulatory requirements for sites outside the UK
Please contact the Research Governance Team for advice on any of the above issues.
Prior to applying for MHRA, Ethics or NHS Trust R&D Approval, RACD (Research Governance Team) will need to confirm that:
- The study protocol complies with Good Clinical Practice standards set out by ICH GCP. Please refer to Cardiff University's SOP-Protocol content and format to meet ICH-GCP standards
- The Patient Information Sheet and Consent Form complies with NRES guidelines.
The trial will also need to have the following in place:
- Investigators Brochure to submit to the MHRA. Please refer to ICH GCP guidelines for further information: International Conference on Harmonisation Guidance on Good Clinical Practice (Topic E6) (CPMP/ICH/135/95)
- An Adverse Event Reporting Procedure (this would normally form part of the Trial Protocol). For further guidance on Adverse Event reporting please refer to:
- Any additional SOPs (e.g. ordering IMP supplies, Data Collection, Source Data Verification, etc)
The Trial Case Report Form and should also be developed at this stage.
You will need to liaise with RACD Contracts Team to ensure that all contracts with trial partners are finalised. For example:
- Funding organisation
- IMP supply company
- 3rd Party organisations involved in trial management
- The model site agreement to be provided to each Centre at the R&D application stage
A delegation of Sponsorship Responsibilities Agreement should be agreed and signed between RACD and the Chief Investigator. Where a Clinical Trials Unit is involved in Trial Management, it may be more appropriate for the Delegation of Sponsorship Responsibilities Agreement to be tri-partite agreement to be signed between the Clinical Trial Unit, the Chief Investigator and RACD (Sponsor).
All clinical trials authorised for conduct in the European Union must be registered on the EudraCT database. Before completing a Clinical Trial Authorisation application and obtaining ethics approval you will require a EudraCT number, which is a reference number unique to your trial.For more information and to apply for a EudraCT number please visit the EudraCT website
To check whether the trial is ready to proceed with obtaining ethics and MHRA approvals, you should use the 'Am I ready to obtain approvals' checklist.
All Clinical trials require a favourable opinion from the National Research Ethics Service (NRES). The Chief Investigator is responsible for obtaining ethics approval.
- Single Centre Trials should normally complete NHS Trust R&D submission prior to MHRA and Ethics submission. Once approval has been obtained from the NHS Trust, an application to the MHRA and Ethics can be made.
- Multi Centre Trials should normally obtain MHRA and Ethics approval prior to submitting to the relevant NHS Trust R&D Offices.
All applications to Research Ethics Committees (RECs) in the UK are made using the NHS REC form in the Integrated Research Application System (IRAS). All applications must be accompanied by the research protocol and relevant documents as per the applicant's checklist (which must also be submitted). Detailed guidance on using the IRAS system is available on the IRAS website
Authorisation to conduct a clinical trial in the European Union requires submission of a Clinical Trial Authorisation application (CTA) to the Competent Authority. The Competent Authority for the UK is the Medicines and Healthcare Products Regulatory Agency (MHRA).
After obtaining a EudraCT number, the CTA application form should be completed using either the IRAS website or the EudraCT website and saved to your computer as an XML file. Detailed information on how to submit an application for Clinical Trial Authorisation is available on the MHRA website.
It must be noted that all correspondence with the MHRA and NRES should be retained in the Trial Master File and a copy provided to the Sponsor.
Research projects must be approved at NHS Trust(s) that are participating in the study, in order for the Trust to fulfil its responsibilities under the Research Governance Framework. Researchers who wish to undertake trials that involve the NHS, NHS patients, their tissue, data or samples, should seek advice from each participating R&D Office before submitting their research study, as each participating R&D Office may have slightly different R&D approval requirements and procedures which will need to be followed.
All applications for R&D approval from NHS organisations are made using the NHS/HSC R&D form in the Integrated Research Application System (IRAS). You must submit an R&D application pack when you need NHS R&D approval. Application packs should consist of:
- the study-wide R&D form generated by IRAS
- the Site-Specific Information form (one for each research site)
- supporting documentation as specified in the R&D submission checklist in IRAS
Contact details for NHS R&D Offices can be found on the NHS R&D Forum website.
Detailed guidance on completing the IRAS form is available from the IRAS website.
For advice on obtaining R&D approval from Cardiff and Vale University Health Board please visit our Cardiff and Vale UHB Approval page
The CI for the study is required to obtain Host Organisation approval (i.e. R&D approval). In the case of Multi centre trials, the CI should inform local PIs that they may proceed with local R&D approval submissions. As part of Host Organisation approval, they must sign and return a Site Agreement. Please contact the Contracts Team for further information.
R&D Approval : Primary Care
In Wales, a central Primary Care R&D Coordinating Office has been established operating a system known as SPARC (Streamlined NHS Permissions Approach to Research – Cymru). All R&D applications relating to primary care should be sent to the co-ordinating office. For further information see the All Wales Primary Care Research Management & Governance Office website.
In England, the National Institute for Health Research (NIHR) Coordinated System for gaining NHS Permission (CSP) is a new system designed to support the application and approvals process for NHS R&D approval for NIHR Clinical Research Network Portfolio studies. For more information see the NIHR website
In all other circumstances applications should be made directly to the participating R&D Office. Contact details for NHS R&D Offices can be found on the NHS R&D Forum website.
Recruitment of patients on to the Trial must not commence without approval to commence from the Sponsor. CI should use the Clinical Trials Toolkit 'Am I ready to commence' checklist to determine if the study is ready to start. Once the Trial is ready begin, contact the Research Governance Team to arrange a Sponsor Initiation Visit. RACD will inspect the Trial Master File in order to verify that the trial management systems are satisfactory. Following a satisfactory Initiation Visit, RACD will issue a Sponsor approval to commence letter.