Why is trial planning important?

A robust trial design is essential to ensure a successful outcome. The trial design should be considered before developing the protocol. This will help ensure that all necessary practical requirements are identified early so that adequate funds are requested.

A well-documented study plan will facilitate the process of developing funding applications, ethics committee and R&D approvals / NHS permissions, and any necessary regulatory approvals.

What does successful trial planning look like?

• Conceptually simple & tailored to the patient group
• Addresses questions of clinical relevance where genuine uncertainties exist
• Avoids unnecessarily complex/restrictive entry criteria to ensure generalisability, where appropriate
• Avoids unnecessarily complex data requirements (resulting from a careful justification of each data point to be collected)
• Ensures the most appropriate choice of control arm (where appropriate)
• Ensures robust allocation concealment (where possible)
• Ensures robust blinding of intervention or appropriately blinded outcome assessments (where appropriate)

What help is available in Manchester for trial planning?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

The North West Research Design Service

Top Tips

Map out the stages to your research project and start the process early as there is lots to do and remember to get your protocol peer reviewed as this will be the ‘trial manual’ you will follow throughout your study or clinical trial – it’s really worth investing the time in this document.
Be sure there is sufficient basic science/early clinical data to justify moving on to a Phase I/II trial.

Why is funding important?

Trials are typically a major financial investment, and as a result securing funding can be a lengthy process. Major funders will need to be assured that the proposed research is important and addresses a clear need, well designed, feasible and scientifically valid, and offers value for money.

The time required to secure funding should be considered in wider development and planning activity, and many funders publish timetables for funding opportunities to assist with this task.

What steps do you need to take to gain funding?

It is recommended that the eligibility requirements of the precise funding scheme are checked before submitting an application, and many Funders offer resources to enable researchers to confirm suitability ‘in principle’ at an early stage.

Researchers are likely to be asked by their funder to demonstrate commitment to involving patients and the public in their team. It may also be a requirement to include a plain English summary, so that the funding proposal can be clearly understood by public contributors.

• It is very important to account for the costs of public involvement in your trial. INVOLVE’s cost calculator is a useful tool and guide to budgeting
• The NIHR Research Design Service may be able to provide a grant to support PPI activities at the proposal stage

Funding for responsible data sharing may be requested from trial funders as part of the funding proposal. A Data Sharing Guidance document has been produced as part of an MRC Hubs for Trials Methodology Research funded research project. This summarises good clinical practice principles to follow when sharing individual participant data from publicly funded clinical trials.

In addition, several Funders offer key documents and resources to explain ‘tips’ to applicants which address key aspects required for success.

Once you have identified a suitable funding stream, it is most likely you will need to obtain costs from a number of locations including the NHS, HEI and research facilities.  It will be important when consulting R&D to define how costs are allocated by differentiating between research costs, NHS service support costs and treatment costs in relation to activities specified in the protocol. The Department of Health’s AcoRD guidance should be referred to in this activity. The Greater Manchester Research Hub will be able to signpost you to the key contacts who will be able to provide specific costs for your trial.

What help is available in Manchester for funding? 

Greater Manchester Research Hub 
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Top Tips 

• When preparing your funding applications, think very carefully about your contracting & costing arrangements:
• Your local NHS & HEI research offices are excellent starting points and remember:
• Start your discussions early with whoever is going to cost your trial activities. It is advisable to do a thorough costing from the start as dramatic changes to research grant costs will not be looked on favourably by the funders.  Think very seriously about (excess) treatment costs and please be mindful of NHS organisations national targets around trial start up and, if involving industry, completing your study or trial to time and target.
• Clinical Trials Units need at least 12 weeks to compete the work for a funding application.

Why is protocol development important? 

A protocol is defined in the Part 1(2) of The Medicines for Human Use (Clinical Trials) Regulations 2004 as: “A document that describes the objectives, design, methodology, statistical considerations, and organisation of a clinical trial”

The protocol also provides information on the background and rationale for a trial and outlines the study plan for that trial. The plan must be carefully designed to safeguard the health and safety of the participants, as well as answer specific research question(s).

What steps do you need to take when developing a protocol?

The protocol describes:

• the type of participant
• the schedule of tests
• procedures
• medications and dosages
• How safety will be monitored
• the duration of the trial
• and should include a definition of the ‘end of the trial’

Protocols (and many other documents produced as part of a trial) should be controlled documents; version numbered and dated using a formalised convention.

Involvement of patients and the public (PPI) helps to shape fundamental aspects of the protocol to ensure it takes into account the needs of participants. INVOLVE have a number of helpful examples which demonstrate the impact of PPI in research.

The NIHR Research Design Service (RDS) may provide support relating to aspects of protocol development such as trial design, choosing appropriate outcome measures and statistical input for researchers based in England.

To support researchers to develop high quality protocols, the Health Research Authority have produced protocol guidance and a template to assist organisations and individuals to improve the consistency and quality of their CTIMPs. The template is in line with regulatory requirements and the SPIRIT guidelines.  Although the template is not mandatory, it contains all the elements that review bodies wish to consider, so protocols which have regard for the guidance and template are less likely to raise queries that can cause delays.  A consideration of section 6 is useful when preparing funding applications and will facilitate the development of the protocol if funding is awarded. It is also worth noting that many research funders have specific requirements for protocol content and presentation that should be considered.

For non-CTIMP research, it is good practice for the protocol to include as much of the information in the topics/sections of ICH GCP E6 and the SPIRIT checklist, as relevant.

What help is available in Manchester for protocol development?

Greater Manchester Research Hub 
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

The North West Research Design Service

NIHR / Wellcome Trust Manchester Clinical Research Facility
0161 906 7500

Why is sponsorship important?

Sponsorship is required for studies under the Research Governance Framework(s) including trials that that fall within the scope of the Clinical Trial Regulations. It may take some time to secure a sponsor(s), so identification of the sponsor must be considered early in the planning process.

For Clinical Trials of Investigational Medicinal Products (CTIMPs), the European Commission Directive 2001/20/EC define the sponsor as: An individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial.

The sponsor therefore is not simply responsible for ensuring there are adequate funds for the trial and for CTIMPs; the Clinical Trials Regulations define legal responsibilities that the sponsor must arrange to carry out. These legal responsibilities should not be confused with liability for the harm of a subject. In 2004, the Department of Health and Universities UK published Responsibilities, Liabilities and Risk Management in Clinical Trials to clarify the implications of the Clinical Trials Regulations.Some host organisations may not be in a position to undertake the role of sponsor for CTIMPs or may only sponsor trials of a certain risk level. It is essential therefore that they are involved at an early stage and that a risk assessment is undertaken at the very start. The process could be defined such that the risk assessment is undertaken on the research proposal and then further refined once the protocol has been drafted.

What is the approvals checklist?

The following checklist is designed as a means of checking that the necessary documentation required for the permissions and approvals process is in place.

The Checklist

• Sponsor(s) identified and agreements for allocation / delegation of responsibilities (if necessary) are in place
• Input from a statistician secured
• Arrangements for a data monitoring committee, steering group and/or management group in place (with consent from members)
• Funding secured
• R&D and local NHS support departments (e.g. pharmacy, labs, radiology etc) consulted and capacity available
• Insurance and indemnity arrangements in place (non NHS)
• Arrangements for trial supplies in place
• Systems in place to ensure trial will be conducted to the principles of GCP and Clinical Trials Regulations
• Arrangements for appropriate Patient and Public Involvement -Patient and public involvement (PPI) is important to ensure that the question proposed is important and relevant to the people it directly affects and that the trial is practical and feasible. There is now a growing evidence base to support the positive impact that PPI can have on participation recruitment and retention in clinical trials.  Many funders will require evidence of genuine involvement as a condition of funding.If you are planning extensive public involvement in your research, you might want to consider assessing the impact of this using a tool such as the Public Involvement Impact Assessment Framework (PiiAF).
• Peer review complete
• Trial risk assessment carried out, trial management systems and monitoring plan/arrangements in place
• Unique trial number and EudraCT number obtained
• Contracts and agreements in place including third party agreements where outsourcing of any trial specific test/services is required
• CVs of investigators (signed and dated)
• Arrangements for pharmacovigilance considered
• Trial Master File established
• Protocol and associated documents (see relevant stations):
  • EudraCT number on all documentation
  • End of trial defined
  • Safety reporting section of the protocol outlining definitions and reporting requirements
  • All written information provided to/viewed by subjects (e.g. Participant information sheets, consent forms, patient diaries, recruitment advertisements) finalised and version controlled
  • All other relevant trial documentation finalised and version controlled e.g. questionnaires, case report forms, trial specific SOPs
  • Investigator’s brochure or SmPC developed/identified

What help is available in Manchester to complete the approvals checklist?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Local research & development offices (based at NHS trusts)

University research offices 

Why is MHRA important?

In the UK, a Clinical Trial Authorisation (CTA) from Medicine and Healthcare Products Regulatory Agency (MHRA) is required for a Clinical Trial of an Investigational Medicinal Product (CTIMP).  For international trials in Europe, an application to the competent authority in each member state is required. Details are specified in Section 2 of EC Guidance CT-1.

What steps do you need to take to get MHRA approval?

Prior to submission to the MHRA, each trial must be registered on the European Clinical Trials Database by obtaining a EudraCT number.

Researchers should apply via the EudraCT website by clicking ‘Access to EudraCT’ and then ‘Create’ and ‘EudraCT number’ before completing the registration form. The unique EudraCT number generated has the format YYYY-NNNNNN-CC, where:

• YYYY is the year in which the number is issued
• NNNNNN is a six digit sequential number
• CC is a check digit

The e-mail containing the EudraCT number should be printed and filed.

As the trial progresses, the EudraCT number will be the main identifier for that trial and should be included on all correspondence (for example when reporting substantial amendments and safety reports).

It is mandatory for clinical trial summary results to be posted in EudraCT within six to twelve months following the end of the trial (depending on the type of trial). It is the sponsor’s responsibility to ensure that this is done.

A fee is also payable to the MHRA (see fees section of the MHRA website).

Non-CTIMP research does not require a EudraCT number.

Detailed information on how to submit the application is available on the MHRA Applying to Conduct a Clinical Trial webpages. The application may be completed via the Integrated Research Application System (IRAS) or directly from the EudraCT Web Site. Applications can now be submitted using the Common European Submission Platform (CESP). 

Note: For some first in human trials where certain risk factors are present, the MHRA will seek advice from an Expert Advisory Group before a CTA application can be made. 

The Clinical Trial Notification Scheme: The MHRA will process the application based on the type of the trial (Type A, B or C) as described in Risk Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products (PDF).

For certain Type A trials, the Clinical Trial Notification Scheme pages of the MHRA web site describe the process and timelines for the CTA application. Once the application is sent to the MHRA, it will be acknowledged with an accompanying note to say that the trial may go ahead after 14 days from receipt of notification if no objections have been raised. The acknowledgement letter will act as the authorisation.

For Type B and C trials, the notification scheme is not applicable and each application will be fully assessed by the MHRA. They will provide an initial response within 30 days of receipt of a valid application, with an average of 14 days for Phase 1 healthy volunteer studies. The MHRA CTA Page lists the documents required for a valid application.

The CTA Application Flowchart (pdf, 11.82 KB) gives an overview of the application process.

Medical Device Trials

There is advice on applications to MHRA for devices on the University of Manchester’s website.  Essentially devices can be developed by researchers and trialled with approval if they are used ‘in house’ i.e. within the host-institution.

Also, remember that mobile phones are also classed as a device and it appears that apps are being considered by MHRA as potential devices and may require an entirely separate application before they are licensed for use. Health and Mobile Medical Apps: A Framework to Assess Risk and Promote Safer Use and guidance for application for approval can be found here.

For non-CTIMP research, a Clinical Trials Authorisation is not required.

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Local research & development offices (based at NHS trusts)

University research offices 

Greater Manchester Clinical Research Network

Why is ethics and HRA approval important?

In the UK, the Health Research Authority (HRA)  exists to protect the rights, safety, dignity and well-being of research participants whilst facilitating ethical research that is of potential benefit to participants, science and society. This is achieved through the review of research taking place within the NHS by NRES Research Ethics Committees (RECs). RECs give their opinion about the proposed participant involvement and whether the research is ethical. Whilst the majority of research conducted within the NHS requires ethical review (see the Governance Arrangements for Research Ethics Committees – A Harmonised Edition for details), including all research involving NHS patients, there are some important exceptions*.

*For exceptions to the requirement for ethical review see the HRA Decision Tool

For all Clinical Trials of Investigational Medicinal Products (CTIMPs), the legal requirement for ethical review is set out in Part 2 of The Medicines for Human Use (Clinical Trials) Regulations. Application to NHS RECs should be made using the Integrated Research Application System (IRAS)

What steps do you need to take to get HRA approval?

Full details of how to apply for HRA approvals are available on the HRA website.

Patient and Public Involvement (PPI): 

Ethics Committees will consider researcher’s plans for PPI as part of the ethical review process. Specific ethical approval does not need to be sought when involving the public in trial design and management activities.

Ethical Approval of Projects Involving Gene Therapy and certain other types of research:

The Gene Therapy Advisory Committee (GTAC) was the national flagged REC for review of clinical trials of stem cell therapies derived from stem cell lines until the end of November 2012. The Health Research Authority (HRA) announced new arrangements for ethics applications in this area, using a system with existing NRES committees. The HRA website should be consulted for more information and updates on latest developments.

The UK Stem Cell Tool Kit gives further guidance on the legislative requirements and processes for clinical trials of stem cell therapies.

The Experimental Medicine Tool Kit provides further guidance on the legislative requirements for experimental medicine* studies in the UK.

What help is available in Manchester with Ethics?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Why is local research and development important?

Within NHS organisations (and some Higher Education Institutions) there are Research and Development (R&D) Departments or Clinical Research Offices. Organisations that work closely together, for example an NHS Trust and a local university may have joint R&D offices. These offices act on behalf of the organisation(s) to facilitate the local management of all research within that organisation.

An NHS R&D Office must give formal permission before a research project can take place within their organisation:

• When acting as the sponsor, NHS R&D offices will be involved in the oversight of the trial by guiding the Chief Investigator and managing the risks associated with any trial initiated.
• When acting as a host organisation, NHS R&D offices facilitate the timely risk management and set up of externally sponsored trials and support the Principal Investigators participating in those trials.

Whichever scenario applies, these offices need to be aware of all projects that involve their organisation’s staff or resources, in order to ensure that:

• Appropriate negotiations are initiated with relevant university or NHS departments (and other third parties)
• Appropriate arrangements are put in place to support the research
• Risk management measures are in place, in particular appropriate insurance or indemnity provision.

What steps do you need to take to obtain local R&D approval?

Researchers are advised to contact their local R&D Office in the early stages of study development so that they can help identify facilities that can provide valuable support.

It will be important when consulting R&D to define how costs are allocated by differentiating between research costs, NHS service support costs and treatment costs in relation to activities specified in the protocol. The Department of Health’s AcoRD guidance should be referred to in this activity.

It is mandatory for all research (CTIMPs and other studies) in the NHS to be conducted in line with the Research Governance Framework(s) and the R&D Office is responsible for ensuring that all research meets these requirements.

The process for applying for NHS/HSC permission will shortly be changing as the Health Research Authority evolves over the coming months Applications for NHS permission in England should be made using the Integrated Research Application System (IRAS) (see also IRAS station). IRAS provides guidance on the completion and submission of the NHS R&D form and NHS SSI forms that is appropriate to the nation(s) participating in the trial. For trials to be conducted across the UK, the NHS permission process should be initiated via the system that is in operation in the part of the UK where the Chief Investigator is located.

Non NHS Sites: Where studies do not involve the NHS (i.e. patients, their data, tissues or NHS resources) then application for NHS permission is not required. However NHS research ethics committee (REC) approval will be required for certain studies (see IRAS guidance). In addition, the investigator should be aware of any local policies relating to the gaining approval from their non-NHS sponsor/host organisation.

Patient Identification Centres (PICs): PICs are organisations from which clinicians or clinical units refer potential participants to a research team based in another organisation, for assessment and possible recruitment to a study. The NIHR web pages contain information on PIC sites and the documents that need to be submitted to the NHS R&D office of a PIC site.

The Research Passport and Honorary Research Contracts: Researchers who have no contractual arrangements with NHS organisations hosting research and who want to carry out research in the NHS (that affects patient care or requires access to NHS facilities) may require a research passport. If the research only requires access to patient identifiable data and does not have a direct impact on quality of care, then only a Letter of Access may be required. To facilitate the process of obtaining Honorary Research Contracts or Letters of Access, the Research Passport scheme has been developed. Researchers should visit the NIHR research passport scheme for more information.

A brief word about medical device trials

If you are undertaking a trial of a medical device, then part of the R&D approval process will more than likely involve a ‘sign off’ from the local trust’s Medical Physics/Engineering Department. This can take time, so it is advisable to speak with your local R&D Manager as soon as possible.

What are the key considerations?

The approvals process is a major part to commencing a clinical trial or clinical research project but there are also a number of key activities that need to be considered in parallel to approvals process. These include:

• Contracting for services associated with your trial
• Ensuring your research team are fully trained to enable them to conduct the trial.
• Ensuring standardised procedures are in place for major components of the trial (e.g. pharmacovigilance, consent, annual reporting etc) as well as trial specific tasks such as taking blood, imaging protocols, administering questionnaires, storing samples, etc)
• Managing Investigational Medicinal Products, calibration and monitoring of trial related equipment etc

What steps do you need to take to address the key considerations?

The following process steps will provide some background and useful information as to what other preparations need to be undertaken prior to recruiting that first trial participant.

What help is available in Manchester with the key considerations?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Greater Manchester Clinical Research Network

Local research & development offices (based at NHS trusts)

University research offices 

Why is contracting third-party services important?

Many parties may be involved in the conduct and management of a clinical trial and it is important that each party has a clear reference of what is expected of them.

Contracts and agreements should be in place prior to the initiation of any trial and should be subject to periodic review to ensure that they remain up to date and relevant.

What steps do you need to take to contract third-party services?

The content of contracts and agreements should include:

• The standards that are applicable (for Clinical Trials of Investigational Medicinal Product (CTIMPs) this would include the Clinical Trials Regulations)
• The roles and responsibilities of various parties
• The procedures to be undertaken
• The lines of communication.

Contracts and agreements can be formed at many levels; internal or external and both legal or non-legal. Examples include but are not limited to:

• Co-Sponsorship Agreements (defining the legal responsibilities taken on by parties under the Clinical Trials Regulations)
• Funding Agreements (terms and conditions related to any funding granted)
• Clinical Trial Agreement/Site Agreements (see UKCRC web pages and NIHR web pages)
• Collaboration Agreements
• Intellectual property Agreements
• Commercialisation Agreements
• Service Level Agreements (with external suppliers such as central laboratories, external statisticians)
• Material Transfer Agreements (handling requirements for material, such as tissue samples, transferred from one organisation to another)
• Pharmacy Technical Agreements (to cover processes applied to the IMP such as packaging, manufacture and radiolabelling)

At the site level, the roles and responsibilities of the Chief investigator, particularly if they are delegated sponsor tasks, should be documented and agreed.

For multi-site trials, the Principal Investigator at each site should understand and accept their particular responsibilities and should document the allocation of all trial tasks, to members of their trial team, using a Delegation Log.

The Greater Manchester Research Hub has a library of template agreements that can be used for sub-contracting with 3rd party providers.

Contact: Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

Why is training important?

It is essential that all clinical trials are carried out to the highest standard.  In addition to GCP training, it is vital that every member of a research team from the Chief Investigator through to research students are appropriately trained as demonstrated by qualification, experience and skill to conduct the duties/activities delegated to them and that appropriate records are maintained that describe the capabilities for each member of the research team.

Sponsors will expect for those involved in their clinical trials to read and fully understand all of their standard operating procedures (SOPs).  This will include whenever an SOP is updated or revised.  In addition to the generic SOPs provided by the sponsor, SOPs or work instructions will need to be created for trial specific activities (e.g. taking blood, sample collection, questionnaire administration etc).

What steps do you need to take to organise training?

GCP Training

The Clinical Trials Regulations require all clinical trials of investigational medicinal products (CTIMPs) to be run to the conditions and principles of Good Clinical Practice (GCP). These regulations define GCP as: “.... a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects.”

Compliance with GCP provides assurance that the rights, safety and well-being of subjects are protected and that the results of CTIMPs (and other clinical research) are credible.

For CTIMPs, the core conditions and principles of GCP were specified in the European Commission GCP Directive 

This Directive was transposed into UK law by means of The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (which amended the Medicines for Human Use (Clinical Trials) Regulations 2004). A summary document can be accessed here outlining the conditions and principles which must be applied when conducting CTIMPs in the UK.

It is recognised however, that there is some flexibility in the interpretation GCP and where appropriate, a risk adapted approach should be considered. See the Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products for more information.

For trials run by commercial sponsors where data are intended to be submitted to regulatory authorities, the ICH (GCP) E6 Guideline is the internationally recognised GCP standard and should be adhered to (in addition to the Clinical Trials Regulations and the European Commission Detailed Guidance Documents). These guidelines have no legal basis in the UK and even though some of the provisions defined in the Clinical Trials Regulations are based on ICH (GCP) E6, there are notable differences, such as the length of time required for the archive of trial documentation.

The MHRA Inspectorate has published the Good Clinical Practice Guide giving information and practical examples relating to the implementation of the Clinical Trials Regulations.

Sponsor Requirements & Trial Specific Training

It is most likely that the sponsor will provide generic Standard Operating Procedures to you at the Site initiation Visit (SIV).  If your trial is non-commercially funded and sponsored, it is quite likely that the CI will be asked to create some trial specific SOPs/work instructions.  The sponsor may provide a template for the CI to populate but if not, the Greater Manchester Research Hub will be able to provide you with templates for use.

For non-CTIMP research, the Research Governance Framework(s) require all research to be run to the principles of GCP.

What help is available in Manchester with ethics?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Greater Manchester Clinical Research Network

University research offices 

Why are supplies and equipment important?

To ensure all regulatory and governance requirements are met, it is essential that investigators obtain advice and support from those with specialist knowledge relating to Investigational Medicinal product (IMP) supplies (for example from a Clinical Trial Pharmacist, Clinical Trials Unit (CTU) or Contract Research Organisation (CRO)).

Advice should be sought early in the trial planning process as requirements may impact on trial design and any funding application.

What steps do you need to take to obtain supplies and equipment?

A Trial Supplies Guide has been developed to:

• Introduce Chief Investigators (and others involved in organising IMP supplies) to the language and complexities surrounding these activities (including a Trial Supplies Checklist).
• To provide Pharmacy staff with a comprehensive guide covering all aspects relating to the manufacture, supply, assembly, labelling, blinding and costing of trial supplies, as well as consideration for the pharmacy documentation required for clinical trials

The status of the IMP used in a clinical trial influences the reference document that may be required. The MHRA Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products gives the following guidance:

“If the IMP is authorised in any EU Member State and is used according to the terms of the marketing authorisation, the Summary of Product Characteristics (SmPC) will replace the Investigator’s Brochure. If the IMP is authorised in an ICH country (USA or Japan) a copy of the prescriber’s information (equivalent to the SmPC) will replace the Investigator’s Brochure.

If this document is originally in a language other than English, an English translation should be provided.

When the conditions of use in the clinical trial differ from those authorised, the SmPC or equivalent should be complemented with a summary of relevant data that support the use of the IMP in the clinical trial. This can be provided as an Investigator’s Brochure or, in some cases, may be incorporated into the protocol.’”

Where an Investigator’s Brochure (IB) is required for a non-commercial trial, it may be supplied by the Marketing Authorisation Holder of the IMP under trial. If it cannot be obtained from the Marketing Authorisation Holder or the IMP is being developed ‘in house’, the sponsor must ensure that an IB is produced.

Trial Equipment

It is entirely possible that your clinical trial will require additional equipment to be used throughout its duration.  In order to ensure it is performing at its optimum, it is essential that it is regularly checked and calibrated to provide assurance that the measurements/functions it is undertaking are accurate and reliable.  The sponsor of the trial will expect each site to maintain and keep records relating to servicing, calibration and any repairs that trial related equipment may undergo.

If the equipment has been provided specifically for the trial, you will need to ensure that it is checked by local ‘medical physics’ or equivalent departments and ‘signed off’ by them before you can start to use it.  Do not underestimate how long this process may take, so it is advisable to speak to your local R&D/Research office as soon as possible, if new equipment is to be used for your trial.

What help is available in Manchester relating to obtaining supplies and equipment?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

University research offices 

Why are trial management arrangements important?

A trial cannot begin until all the relevant permissions and approvals have been obtained. For Clinical Trials of Investigational Medicinal Products (CTMIPs), Regulation 13 of The Medicines for Human Use (Clinical Trials) Regulations requires specific documentation to be in place before a Investigational Medicinal Product (IMP) can be released.

Before commencing the trial, the Chief Investigator in conjunction with the sponsor, will ensure that all trial documentation has been prepared and version controlled. For multi-site trials, the Chief Investigator will ensure that each Principal Investigator is provided with all relevant, version-controlled documents before commencing recruitment.

For clinical trials of investigational medicinal products it is a requirement that systems are in place to enable the identification, recording, reporting and analysis of safety information so that any safety signals that arise during a trial are quickly identified and acted upon.  Finally, to ensure consistent and reliable data generated during a clinical trial, appropriate procedures need to be in place that cover data collection, verification, validation, storage, analysis and reporting.

What trial management arrangements are required?

The following sections provide further detail relating to: essential documentation and its storage, Pharmacovigilance/Safety Reporting, and data management activities and where advice and support can be found to support and address each component.

What help is available in Manchester in relation to trial management arrangements?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Greater Manchester Clinical Research Network

Local research & development offices (based at NHS trusts)

University research offices 

Why are trial documents important?

Good Clinical Practice (GCP) requires that all clinical trial information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified.

Essential documents are:

“…those which enable both the conduct of the clinical trial and the quality of the data produced to be evaluated; and show whether the trial is, or has been, conducted in accordance with the applicable regulatory requirements”

Many essential documents are filed in a Trial Master File / Investigator Site File.  Some, essential documents may also be source documents, which are often generated as part of the subject’s medical care and therefore documented and archived in medical records and other service departments.

A Trial Master File(TMF) should be set up at the beginning of a trial. The essential documents that make up the file should be kept in a secure but accessible manner.  A well-kept TMF can help with efficient trial management and can facilitate the reconstruction of the conduct of the trial during the audit/inspection process.

The TMF should be held at the coordinating site (usually the Chief Investigator’s office or Coordinating Centre) and for multi-site trials, copies of relevant documents should be kept at each participating site in an Investigator Site File(ISF).  Most sponsors will provide guidance on the content and set up of the TMF/ISF based on their local policies/procedures.

The TMF/ISF should be maintained throughout the course of the trial and it should be clear who has been given the task of maintaining it, for example by indicting this role on the Delegation Log.

What steps do you need to take to ensure you have the correct trial documents?

The European Commission has published Detailed Guidance on the Content of a Trial Master File and Archiving and is primarily based on ICH GCP E6 Section 8. This document includes an explanation of the purpose of each essential document and whether it should be retained by the sponsor, the investigational site or both.

Source data and other essential documents may be kept in either paper or electronic format. The EMA published a document in 2010: Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials

A number of European Commission Guidance Documents have been published which serve to illustrate what would be evaluated during an inspection of a clinical trial and therefore what documentation would be required to enable that evaluation (see Chapter IV- Inspections: Annex I-V)

What help is available in Manchester with trial documents?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Greater Manchester Clinical Research Network

Local research & development offices (based at NHS trusts)

University research offices 

Why is pharmacovigilance important?

Pharmacovigilance (PV) is the science relating to the detection, assessment, understanding and prevention of the adverse effects of medicines. Systems must be in place to enable the identification, recording, reporting and analysis of safety information so that any safety signals that arise during a trial are quickly identified and acted upon.

What steps do you need to take to ensure pharmacovigilance?

For Clinical Trials of Investigational Medicinal Products (CTIMPs), the sponsor’s responsibilities for PV are defined in Part 5 of the Medicines for Human Use (Clinical Trials) Regulations SI 2004 1031.

European Commission Detailed Guidance CT-3 2011 defines the requirements for CTIMPs including the terminology associated with PV based on the assessment of seriousness, causality and expectedness of an adverse event. A safety reporting flowchart has been developed as part of the Toolkit to provide an overview of the assessments required.

Comprehensive guidance covering all aspects of PV for non-commercial trials (including when a risk adapted approach may be appropriate) can be found in the Joint Project Workstream Document: Pharmacovigilance.

The Investigational Site: For all trials, the investigator should make all staff aware of any safety reporting requirements and have systems to ensure all relevant events are detected, recorded and notified in accordance with the protocol (see Safety Reporting station).

Staff should be made aware of these requirements through GCP training and/or knowledge of local procedures or policies.

What help is available in Manchester with Pharmacovigilance?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Local research & development offices (based at NHS trusts)

University research offices 

Why are data management activities important?

ICH GCP states that, “All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.”  Data management activities  involve the collection, cleaning, and management of subject data in compliance with regulatory standards. In so doing, it provides high-quality data by keeping the number of errors and missing data as low as possible and allows maximum data for analysis.

What steps do you need to complete data management activities?

From the protocol, you will need to produce a case report form (CRF) to capture study data and a data management plan to ensure adherence to data collection and review processes.  Case report forms can either be paper based or electronic, the latter are commonly used in multi centred trials but more trials are moving over to them.  You will then need to consider how you will collect, store, verify, validate and interpret your clinical trial data.

The regulations are extremely rigorous when it comes to this element of the clinical trial. It is no longer acceptable to store data within spreadsheets or on bespoke databases.  It is highly recommended that you involve the Clinical Trials Unit with this aspect of your trial as they have the systems set up to meet the regulatory standards.

What help is available in Manchester relating to data management activities?

Greater Manchester Research Hub
Dr Lloyd Gregory
0161 306 0111
lloyd.gregory@manchester.ac.uk

The Manchester Clinical Trials Unit 
Philip J Barley, Associate Director
0161 918 7454
philip.barley@christie.nhs.uk

Local research & development offices (based at NHS trusts)

University research offices 

Congratulations!

You have now completed your journey through the Greater Manchester Routemap for Clinical Trials, and you should feel more ready to move your trial forward.

Don’t forget, you can always check back to the map if you need information or resources, or get in touch with one of the contacts highlighted within the content.