Research Regulations
Guidelines for Good Clinical Practice in Clinical Trials (1998).
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.
Successful trials often share similar characteristics. They are:
• Conceptually simple and tailored to the patient group
• Address questions of clinical relevance where genuine uncertainties exist
• Avoid unnecessarily complex/restrictive entry criteria to ensure generalisability, where appropriate
• Avoid unnecessarily complex data requirements (resulting from a careful justification of each data point to be collected)
• Ensure the most appropriate choice of control arm (where appropriate)
• Ensure robust allocation concealment (where possible)
• Ensure robust blinding of intervention or appropriately blinded outcome assessments (where appropriate).
It is important to collaborate with a statistician who can help with:
• Designing your trial
• Choosing an appropriate outcome
• Providing justification of the sample size
• Advising on appropriate randomisation methodology
• Drawing up a statistical analysis plan
• Handling and structuring collected data
• Preparing and presenting interim reports to Data Monitoring Committees (DMCs), if applicable.
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).
The National Context:
When initiating a trial, researchers should familiarise themselves with the framework in place for conducting trials. In particular:
1) The role of the National Institute of Health Research (NIHR), the process and criteria for inclusion of research on the NIHR Clinical Research Network Portfolio and the importance of public and patient involvement when conducting research.
The NIHR Research Design Service (RDS) supports researchers in England to develop and design high quality research proposals for submission to NIHR and other national, peer-reviewed funding competitions for applied health or social care research (see Funding Proposal station).
2) The role of the UK Clinical Research Collaboration (UKCRC), which provides information on the infrastructure for research in the UK. Their web pages include information on Clinical Research Network and Clinical Trial Units (CTUs), including the process for identifying CTUs that may have expertise in coordinating multi-site research in different disease areas or with different trial designs (see UKCRC Registered CTU Networks).
3) The critical path for undertaking a clinical trial can be complex. The RDS Research Process Flow Diagram gives an overview of the process. The positioning of the stations on the route maps within this Toolkit also indicate which activities can be conducted in parallel and which activities should be completed before moving on the to the next stage. For those new to managing trials, the NIHR Trial Managers Network (TMN) is a source of practical support and guidance on the trial management process.
4) The MRC HTMR Network promotes and encourages collaborative methodological research relevant to trials, with the aim of accelerating implementation of the most effective and appropriate methods. It supports workshops, conference and training in trials methodology, in addition to acting as a resource to highlight events and courses across the UK.
The MRC HTMR Network also collates outputs from various projects and initiatives under their “Guidance Pack” for trials. The Network and individual Hubs also offer assistance to colleagues based in Clinical Trials Units and the Research Design Service when they receive enquiries, through the Methodology Advisory Service for Trials.
Further reading:
• HRA Guidance on questions that need answering when designing clinical trials: The Health Research Authority has published useful guidance to clarify which questions researchers, sponsors, peer reviewers, and ethics committees should ask when planning or reviewing clinical studies.
• NIHR Trials Overview: A website resource pulling together information and advice on key trials related activity including methods.
• MRC Ethics Series: Good Research Practice: Information published by the MRC giving guidelines on conducting research with human participants and their tissues and data
• Planning a Randomised Controlled Trial: Points to Consider : A paper summarising some of the trial activities that would need to be considered
• The NHS Research & Development Forum: The NHS R&D Forum is a network for those involved in managing and supporting R&D in health and social care. Information on key activities and developments is regularly updated.
• In England, SOPs developed by sponsor and host organisation conducting studies in should meet the requirements of the Research Support Services (RSS) framework and RSS documents relevant to this station include:
o Annex4-P02-Planning Toolkit for PARTICIPATING Organisation, May 2011.
o Annex5-S05-Planning Toolkit for SPONSORING Organisation, May 2011.
• Trainees Clinical Trial Guidance Guidance to support NIHR trainees interested in getting involved in clinical trials
• DIRUM is an open-access Database of Instruments for Resource Use Measurement.
• Recommendations for the design of MAMS (multi-arm multi-stage) trials.
• Avery et al. (2017) outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. Ten top tips for developing and using progression criteria for internal pilot studies are proposed.
• Gamble et al. (2017) recommend a minimum set of items that should be addressed and included in Statistical Analysis Plans for clinical trials.
Lancet Series on Research Waste:
• Avoidable waste in the production and reporting of research evidence by I Chalmers & P Glasziou.
• Increasing value and reducing waste in research design, conduct, and analysis by J Ioannidis et al.
Other Toolkits available:
• Data and Tissue Toolkit: Practical help with the legislative and good practice requirements relating to the use of personal information and human tissue samples in healthcare research in the UK
• Stem Cell Toolkit: A regulatory tool for those conducting stem cell research in the UK.
• Experimental Medicine Toolkit: For investigators, R&D Managers and ethics committees involved in experimental medicine studies.
Further resources on Patient and Public Involvement:
• INVOLVE is a national advisory group that supports public involvement. The INVOLVE website has a wealth of useful resources including briefing notes for researchers.
• NIHR Public Involvement Pages.
• Two papers from the EPIC study (Evidence base for Patient and Public Involvement in Clinical trials) provide evidence to inform trial teams in planning for PPI in trials and optimising the impact of PPI.
• The People in Research website can be used to help find public contributors to involve in research, or for public contributors to find opportunities to get involved in research.
• The Joint Health and Social Care Regulators’ Patient and Public Involvement Group have produced a useful handbook on good practice in PPI.
• Healthtalk.org showcases a range of different experiences in healthcare including participation and involvement in health research.
There are a number of steps to follow before a trial can commence. The first step is to confirm whether it falls within the scope of the European Directive (2001/20/EC) (PDF, 152 KB). This Directive was transposed into UK law by means of The Medicines for Human Use (Clinical Trials) Regulations 2004, which together with its amendments are referred to as the Clinical Trials Regulations within this Toolkit.
The Clinical Trials Regulations cover only investigations/studies which are undertaken to ascertain the efficacy or safety of a medicine in human subjects. Non-interventional trials are excluded from the Regulations. To classify a trial as non-interventional, it must meet all of the following criteria:
• involves products with a marketing authorisation that are prescribed in the usual manner and used in accordance with the authorisation;
• when the patient is assigned to a therapeutic strategy within current practice and not according to a protocol;
• the diagnostic or monitoring procedures are only those ordinarily applied to the therapeutic strategy;
• and epidemiological methods are used to analyse the data.
(defined in full in column E of the MHRA algorithm linked below).
If a study is not for the purpose of ascertaining the effects of or reactions to a product and the product is simply being used as an aid or tool in the study, it is not a clinical trial covered by the Regulations. For example, in the case of the study of blood flow involving the infusion of vasoactive substances, if the purpose of the study is to monitor the effects of a particular substance to see if it is effective in achieving a particular physiological effect, then it is not a clinical trial. If the infusion is for the purpose of modifying the rate of flow for a therapeutic indication such as claudication, it would be deemed a trial under the Directive as the purpose of the study is to establish the efficacy of a particular medicine.
A Clinical Trials Regulations Flowchart (pdf, 76.83 KB) has been developed which describes the relationship between the EU Directive and UK regulation including a brief description of each regulation. Any trial that falls within the scope of Directive 2001/20/EC is known as a Clinical Trial of an Investigational Medicinal Product (CTIMP).
The Medicines and Healthcare Regulatory Agency (MHRA) is the competent authority that regulates CTIMPs in the UK. The MHRA web pages describe the difference between Investigational Medicinal Products (IMPs) and Non-Investigational Products (NIMPs) and contains an algorithm (PDF) designed to help researchers determine if their trial is a CTIMP.
Researchers planning a CTIMP should be familiar with the MHRA Clinical Trials Pages to help ensure all legal requirements are considered.
Some host organisations may not be in a position to undertake the role of sponsor for Clinical Trials of Investigational Medicinal Products (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.
Risk Adaptation
The MHRA have implemented a scheme for defining the risks associated with each clinical trial by adopting a dual strategy:
1. Defining the risks of the IMP using a simple IMP risk categorisation (Type A,B and C) based on marketing status and standard medical care
2. Defining the risks associated with trial conduct by examining the trial design, population and procedures to identify specific areas of vulnerability and to determine how any risks can be mitigated.
The Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products has been published as part of the MHRA Good Clinical Practice Forum to help sponsors undertake this process.
The MHRA web site gives further information with a ‘Frequently Asked Questions’ thread on the MHRA GCP forum relating to risk adaptation.
Further reading & Workstream Documents:
• Sponsorship station.
• Trials Management & Monitoring station.
• Joint Project Pharmacovigilance Document (pdf, 344.05 KB).
• Trials Supplies station.
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.
Before initiating a trial, the sponsor should define, establish and allocate all trial-related duties and functions. The NHS R&D Forum Sponsorship Principles document (pdf, 103.44 KB) provides a comprehensive summary of the legal responsibilities that an organisation sponsoring a CTIMP must arrange to carry out. This document also describes various models of sponsorship that are possible under the Clinical Trials Regulations and the allocation of responsibilities, duties or functions.
For CTIMPs, the person(s) responsible for the sponsor’s functions must be named on the Clinical Trial Authorisation (CTA). If the sponsor of a CTIMP with sites in the European Economic Area (EEA) does not reside within the EEA, a legal representative should be appointed. Further guidance can be found in the Sponsorship Principles document which also includes advice and future developments for UK sponsors of international CTIMPs.
As of 21 July 2014, sponsors are also responsible for the mandatory posting of clinical trial summary results within EudraCT. Results should be submitted within six or twelve months following the end of a trial, depending on the type of trial.
Sponsor approval may be sought for data sharing requests. A Data Sharing Guidance document has been produced as part of an MRC Hubs for Trials Methodology Research funded research project, which summaries good clinical practice principles to follow when sharing individual participant data from publicly funded clinical trials.
Further reading:
• In England, NHS organisations that sponsor trials, conduct these activities in line with The Research support Services Framework. Please see Annex 5 of the Research Support Services Framework Documents.
• Resources relation to Indemnity and Insurance:
• Insurance and compensation in the event of injury in Phase I clinical trials: Guidance developed by the Association for the British Pharmaceutical Industry, the BioIndustry Association and the Clinical Contract Research Association, in consultation with the Department of Health and the National Research Ethics Service.
• EudraCT trial results: modalities and timing of posting document
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). The protocol describes:
• the type of participant
• the schedule of tests
• procedures
• medications and dosages
• the duration of the trial
• and should include a definition of the ‘end of the trial’ (see End of Trial Declaration station).
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. Useful information and resources about PPI can be found in the Trial Planning & Design station.
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 download 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 (Standard Protocol Items: Recommendations for Interventional Trials). 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.
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.
Both SPIRIT and the NIHR HTA Programme endorse the COMET database which contains information on published and ongoing core outcome set studies, and is regularly updated.
DIRUM is an open-access database of resource-use questionnaires for use by health economists involved in trial-based economic evaluations. DIRUM also provides a repository of methodological papers related to resource use and cost measurement.
Information on protocol review and signoff can be found in the Final Protocol station.
Further reading:
• Unique Trial Number station
• EudraCT Number station
• Final Protocol station
• Substantial Amendment station
• SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) is an international initiative that aims to improve the quality of clinical trial protocols
• The Research Support Services Framework: In England, NHS organisations that sponsor trials, conduct activities in line with the RSS Framework. Key document: RSS Framework-Annex5-S03-Ensure study protocol is managed (May 2011)
• Recommendations for the design of MAMS (multi-arm multi-stage) trials
• Gamble et al. (2017) recommend a minimum set of items that should be addressed and included in Statistical Analysis Plans for clinical trials.
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 (2005/28/EC) (PDF, 68 KB). This Directive was transposed into UK law by means of The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (PDF, 71 KB) (which amended the Medicines for Human Use (Clinical Trials) Regulations 2004). A summary document can be accessed here (pdf, 84.35 KB) 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 of 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 (PDF, 247 KB) for more information.
For trials run by commercial sponsors where data are intended to be submitted to regulatory authorities, the ICH GCP E6 (R2) 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).
The MHRA Inspectorate has published the Good Clinical Practice Guide giving information and practical examples relating to the implementation of the Clinical Trials Regulations.
For non-CTIMP research, the Research Governance Framework(s) require all research to be run to the principles of GCP.
Participating Sites Responsibilities:
For a multi-site trial, the person with overall responsibility for the trial at each site is defined as the Principal Investigator. Guidelines for GCP, from the perspective of the Principal Investigator, are detailed in Section 4 of ICH GCP E6 (R2).
The sponsor should ensure that each site is aware of all regulations and quality standards that apply to CTIMPs by:
1. Specifying the standards that must be adhered to in any site agreements
2. Ensuring that site staff have received GCP and Clinical Trials Regulation training commensurate to their role.
Serious Breach of GCP/Protocol:
The Clinical Trials Regulations require the reporting of serious breaches of GCP or the protocol (regulation 29A of S12004-1031 as amended). Guidance on the definition and reporting requirements can be found on the MHRA web pages: Serious Breach and Good Clinical Practice Reporting. In the UK, serious breaches should also be reported to the relevant ethics committee at the same time as the report to the MHRA, in accordance with Research Ethics Committee Standard Operating Procedures.
Sponsors of CTIMPs should ensure the requirement to report serious breaches to the MHRA and the ethics committee is incorporated into their standard operating procedures to ensure all relevant staff are aware of this legal requirement. This should include detail of how site staff are made aware of requirements (via training or protocol procedures). Host organisations and other parties working with the trial sponsor may also need to consider their own mechanisms for reporting serious breaches (including arrangements for reporting serious breaches directly to the MHRA if the sponsor is in breach).
For non-CTIMP research, serious breaches of GCP or the protocol should be reported to the relevant ethics committee in accordance with the Research Ethics Committee Standard Operating Procedures.
Further reading:
• Ongoing Management & Monitoring station
• Conditions and Principles of Good Clinical Practice Summary Document (pdf, 84.35 KB)
• The MHRA Good Clinical Practice Guide
• WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects
Appropriate planning before the trial and adequate oversight and monitoring during the trial will help ensure that trial subject safety is maintained throughout the trial and that there is accurate reporting of results at its conclusion.
The sponsor is responsible for ensuring that robust trial management systems are put in place. The monitoring of a trial is one of the key activities undertaken as part of the trial’s management. The MHRA accepts a risk-adapted approach to trial management and the advice specific to trial monitoring can be found in Appendix 2 of The Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products.
Risk-adapted trial management addresses the question:
•What are the critical processes and critical data for this trial and how best can any risks and/or vulnerabilities identified in these areas be mitigated?
This question should be considered early in the protocol design stage so that processes to proactively manage those aspects of the trial that are critical to quality can be put in place. The US Clinical Trials Transformation Initiative (CTTI) have produced guidance (based on Quality by Design principles) that provides a useful framework for this process.
Where trial management activities are contracted out to third parties, the sponsor must implement procedures to ensure appropriate oversight of all delegated functions. This can be achieved by:
a) Assessing that individuals or organisations delegated trial management functions are appropriately qualified and competent to perform those functions.
b) Ensuring all parties are aware of their roles and responsibilities (for example by clearly defining them in contracts and agreements).
c) Maintaining lines of communication to ensure the obligations of all parties are being met (for example by receiving progress reports).
Documentation should be in place to describe all key processes. This ensures that those performing tasks have a clear plan of what, when and how trial activities are undertaken and also enables auditors/inspectors to historically reconstruct all trial management activities.
The following provide further information and guidance on trial management:
• The Summary of Trial Management Systems Workstream Document (pdf, 125.32 KB) gives an overview of the activities associated with trial management as well as the requirement for oversight and documentation of those activities.
• The Monitoring Procedures Workstream Document (pdf, 113.07 KB) gives further information on the types of monitoring a sponsor may implement (for example on-site monitoring or central statistical monitoring) and the documentation of all aspects of the monitoring process. Further examples of risk adaptation are also provided in the following Joint Project Workstream Documents:
– Trial Scenarios in Monitoring (pdf, 127.81 KB) which illustrates the approach to monitoring applied to five very different trials
– Trial Monitoring Option Checklist (pdf, 14.92 KB) is a tool used in conjunction with the other resources to help define and develop the strategies for each trial
• The MHRA GCP Guide outlines the expectations for trial management and monitoring and provides a detailed description of all key processes and many examples of risk adaptation.
• The Trial Managers Network (TMN) is a source of practical support and guidance on the trial management process and has published comprehensive guidance: A Guide to Efficient Trial Management.
• The MRC HTMR Network host a series of webinars on trial conduct including Monitoring trials efficiently: The role of central statistical monitoring.
• Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines recommend that an accurate record of patients considered for RCT participation is maintained. The SEAR (Screened, Eligible, Approached, Randomised) framework provides a systematic way to record the flow of potential participants through the recruitment process to support better recruitment practices in clinical trials.
• Guidance on maximising the impact of qualitative research in feasibility studies for RCTs was developed to help researchers consider the full range of contributions that qualitative research can make in relation to their particular trial.
• The use of qualitative methods to inform Delphi surveys in core outcome set development identifies some issues for COS developers to consider.
• Developing and using progression criteria for internal pilot studies: Avery et al. (2017) outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase.
Further reading:
• The GCP Inspectors Working Group have published a number of documents relating to trial processes:
– Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples (PDF, 135 KB)
– Draft Reflection paper on the Use of Interactive Response Technologies (Interactive Voice/Web Response Systems) in Clinical Trials (PDF, 127 KB)
– Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials (PDF, 127) KB
•In England, procedures developed by NHS sponsors conducting trials should meet the requirements of the Research Support Services (RSS) framework documents: See RSS Framework-Annex5-S09-Ensure study oversight (May 2011).
•A Data Sharing Guidance document has been produced as part of an MRC Hubs for Trials Methodology Research funded research project. This summaries good clinical practice principles to follow when sharing individual participant data from publicly funded clinical trials.
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.
The EMA has published Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials (2017) which has been prepared to assist sponsors and investigators to comply with the requirements of the Clinical Trials Regulation (EU) No 536/2014.
Electronic Source Data
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 (PDF, 127 KB).
For sites considering a move from paper medical records to electronic health records (eHR), the MHRA have produced a position statement on the implementation of eHR systems to ensure compliance with the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended). The position statement details common problems found with eHR systems during GCP inspection and provides a comprehensive list of factors to consider when trial sites are establishing an eHR system.
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).
Further reading:
• Trial Master File station
• Archiving station.
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.
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 (PDF) 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.
Pharmacy Assurance
On 15 October 2018, the HRA launched a Pharmacy Assurance process for studies involving Investigational Medicinal Products (IMPs) which has been tested and is going through a phased roll-out across the UK. The process involves the completion of one single pharmacy technical review per study, which can be used by all participating sites. This streamlined approach to pharmacy assessment will allow local NHS/HSC organisations to assess and confirm local capacity and capability more effectively, providing substantial benefits to efficient study set-up. The HRA website provides further information.
Further reading:
•Trial Supplies Guide
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.
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 (pdf, 180.98 KB) 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.
Further reading & Workstream Documents:
• Joint Project Workstream Document: Pharmacovigilance Comprehensive guidance for CTIMPs
• Safety Reporting station: Outlines the safety reporting requirements once a trial has commenced
• Trial Supplies station: For information on requirements for the Investigators Brochure
• The MHRA Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products: Appendix 1, Section 4 – Risk adaptation relating to safety surveillance.
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 ensure all relevant approvals are in place (see R&D Submission station) 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 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.
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.
Organisations and individuals that have responsibilities for clinical trials (or other types of study) in the NHS should ensure that research is conducted in accordance with principles of good practice in the management and conduct. The Health Research Authority and the health departments in Northern Ireland, Scotland and Wales have developed the UK Policy Framework for Health and Social Care Research (2017) which has replaced the separate Research Governance Frameworks in each country.
The NHS R&D Forum website has a list of R&D contact details and further resources on research governance.
Further reading:
• R&D Submission station
• Contract & Agreements station
• UKCRC Information page – Research Passport.
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.
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.
Further reading:
• Protocol Development station.
• RD Info: HRA web pages related to funding.
• National Institute for Health Research (NIHR) Research Programmes: Links to main NIHR research programmes’ site from where you can access specific information on all the NIHR programmes and funding streams.
• Medical Research Council (MRC) Funding Opportunities.
• Wellcome Trust Funding.
Peer review is where a number of ‘experts’ examine the proposed trial to consider aspects such as design quality, feasibility, acceptability and importance of the topic etc. ‘Experts’ in this context will usually include views from relevant clinicians, allied health professionals and other professional groups, methodologists, patients and members of the public.
If an application for external funding has been submitted, then peer review will be undertaken as part of this process.
If external funding is not required, and therefore peer review has not been conducted as part of the funding process, the sponsoring organisation will be able to assist with this matter.
It is important to note that both ethical approval and NIHR Portfolio adoption (if appropriate) will require sufficient demonstration of appropriate peer review.
If funding for a trial is required, it is important to consider that the process of applying and securing funding may take some time. This time should be factored into planning and related activities.
A wide range of bodies fund health and social care research and the HRA funding webpage provides information on a number of the key funding streams. 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.
Once you have received confirmation of a funding award from your Funder, they will require you to complete a number of requirements and activities before the trial can formally start. Some of these requirements will be covered in later Toolkit stations, and others will be specific to the Funder. It is important to stay in contact with the Funder at this stage, and provide a timely response to requests and keep them informed of developments and issues.
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 GCP Inspection Working Group have produced a ‘Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials’ (March 2017), to assist sponsors and investigators to comply with the requirements of the Clinical Trials Regulation (EU) No 536/2014. In addition, the MHRA FAQs for Trial Master Files (TMF) and Archiving provide further guidance on their expectations when scanning paper documents for electronic archive.
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 indicating this role on the Delegation Log.
The European Commission has published Recommendation on the Content of a Trial Master File and Archiving* and is primarily based on ICH GCP E6 (R2) Section 8. Some documents must be in place before a trial is opened, some are generated as the trial progresses and others are added to the file only at the end (e.g. analysis codes and DMC closed reports and minutes). In addition to the guidance above, researchers may also be required to file any trial documentation specific to local policies/procedures.
*In certain trials, some of the documents listed may not be available or applicable. The MHRA Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products has been published to help sponsors define a risk-based approach. See page 17 for possible adaptation relating to study documentation and filing. This approach is supported by ICH GCP E6 (R2) which now includes the following statement, ‘Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial.’
For non-CTIMP research, it would be good practice to file any document that meets the definition of an essential document. Sponsors and host organisations may provide specific guidance on content of files in their policies/procedures.
Further reading:
• Trial Documentation station
• Audit station
• MHRA Inspection station
Trial Registration:
Each clinical trial must have a unique trial number. This requirement is cited in a number of publications including:
1. The Declaration of Helsinki of the World Medical Association (revised October 2013 Brazil) states: “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.”
2. The International Committee of Medical Journal Editors (ICMJE) stipulated that from July 1st 2005, “no trial will be considered for publication unless it is included on a clinical trials registry so it can be tracked from initial protocol through to publication.”
The World Health Organisation (WHO) regards trial registration as the publication of an internationally agreed standard dataset about a clinical trial on a publicly accessible database managed by a registry conforming to WHO standards. The standard dataset is published by the WHO International Clinical Trials Registry Platform (ICTRP).
The ISRCTN registry helps researchers fulfil research transparency and result dissemination objectives, as per the requirements set out by the WHO ICTRP and the International Committee of Medical Journal Editors (ICMJE), by listing the basic set of data items deemed essential to describe a study at inception and by providing the unique identification number necessary for publication.The NIHR Portfolio Database facilitates ISRCTN registration for eligible studies. Additional information can be found on ISRCTN registration on the Clinical Research Network. Alternatively, trials may be registered at ClinicalTrials.gov.
The EudraCT number is an additional mandatory reference number allocated by the European Medicines Agency (EMA) for CTIMPs authorised on or after 1 May 2004 (see EudraCT Number station).
Guidance on trial registration and research project identifiers can be found on the HRA webpages.
Further reading:
• EudraCT Number station.
• AllTrials – What does all trials registered and reported mean?
• BMJ Editorials: All trials must be registered and the results published.
All Clinical Trials of Investigational Medicinal Products (CTIMPs) must be registered on the EudraCT database. This database has been established to:
• support supervision of CTIMPs
• facilitate communication between competent authorities
• link with other databases such as EudraVigilance and the EU Clinical Trials Register.
Each trial must be issued with a unique EudraCT number.
Researchers should apply via the EudraCT website by clicking ‘Login 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.
Non-CTIMP research does not require a EudraCT number.
Further reading:
• Unique Trial Number station
• Protocol Development station
• Ethics Submission station
• Clinical Trial Authorisation Submission station.
For UK trials, the Chief Investigator will approach a potential sponsor (often through a formal registration process) who will assess the operational risk the trial poses before confirming sponsorship. For NHS sponsors, this is usually performed by the NHS R&D office of that organisation. Sponsorship will only be granted once any issues raised by the risk assessment have been addressed. The sponsorship letter should be retained in the Trial Master File.
The sponsor’s signature is required on both the application for ethical approval and for MHRA authorisation.
Other parties, including trial funders and host organisations conducting the trial will also require documented assurance that an organisation has accepted the role of sponsor and the obligations and responsibilities of this role.
Non-commercial trials that fail to meet their targets often result in a request for further funding or may not achieve a statistically significant result. It is important to ensure that feasibility assessment and recruitment planning are considered during the study design and planning stage of a trial. For larger trials, the sponsor should consider, during the funding process, whether a feasibility or pilot study should be undertaken.
The Association of Medical Research Charities and the NIHR Medicines for Children Research Network have produced Points to consider when assessing the feasibility of research. The US Clinical Trials Transformation Initiative (CTTI) have published a suite of Recommendations and Tools for Recruitment Planning that provide a useful framework.
MRC Hubs for Trial Methodology Research (MRC HTMR)
The MRC HTMR have published a range of material relating to feasibility and recruitment including:
• Guidance on maximising the impact of qualitative research in feasibility studies for RCTs was developed to help researchers consider the full range of contributions that qualitative research can make in relation to their particular trial.
• The QuinteT Recruitment Intervention (QRI) provides a flexible way of understanding recruitment difficulties and producing a plan to address them while ensuring engaged and well-informed decision making by patients. A review of qualitative researchprovides further insights into barriers to recruitment.
• A broad range of Tips to consider when optimising recruitment of patients to clinical trials has been produced by the Recruitment Working Group of the MRC HTMR.
• This review and synthesis of qualitative research examining the perspectives of patients and health professionals provides a conceptual framework to help researchers improve recruitment to depression trials.
Investigator Selection
For multi-site trials, the careful selection and evaluation of investigator sites is critical for the successful completion of a trial within budget, timelines and to ensure the generation of high quality data. Factors that should influence investigator site selection include:
• Interest in the research question
• Experience and qualifications of the investigator
• Sufficient staff to conduct the study and their experience and qualifications
• Availability of suitable patient population:
o Anticipated rate of patient recruitment (determined through feasibility assessments)
o Conflicting studies (competing for the patient population and potentially introducing recruitment bias)
• Adequate time to conduct and oversee the trial
• Adequate facilities:
o Availability of any specialised diagnostic or therapeutic equipment required by the protocol
o Adequate space and storage conditions (including archive)
o Available resources in NHS support departments
• Track record with similar trials previously
• Geographic location
• Contractual and budgetary negotiations and arrangements.
When undertaking site selection, the preparation of ‘reserve’ investigator sites (so that the trial may be extended to these sites if recruitment issues arise) should be considered as part of proactive trial planning.
Patient and Public Involvement (PPI):
The CTTI recommendations above stress the importance of patient and public engagement to improve trial success. The initiative includes a Stakeholder Identification and Analysis Tool to support this process. One study from King’s College London, published in the British Journal of Psychiatry showed that trials with higher levels of PPI were 4.12 times more likely to recruit to target. PPI can help shape a number of factors that can improve trial feasibility and recruitment by addressing questions such as:
• Will the proposed recruitment strategy work?
• How could it be made easier for a patient to participate?
• How likely are participants going to accept the study schedule/requirements?
Further reading:
• UK Clinical Trial Gateway provides potential research participants with information about trials running in the UK, including how to locate and contact trials of interest.
• Frequently Asked Questions on Data Requirements on Performance in initiating and Delivering Clinical Research – An NIHR document explaining the importance of recruitment on time and target.
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.
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) – See Trial Supplies station.
For non-commercial trials conducted in England, the HRA Statement of Activities may be used as the agreement between the sponsor and a participating site and can be found on the HRA website.
At the site level, the roles and responsibilities of the Chief investigator, particularly if they are delegated sponsor tasks, should be documented and agreed (see Sponsorship station).
Further reading:
• Research Support Services Framework documents:
o Annex4-P04-Setup and control external agreements (May 2011);
o Annex4-P05-Setup and control internal agreements (May 2011);
o Annex5-S07-Provide and manage agreements (May 2011).
Before seeking approvals to start a trial, the protocol must be finalised, as this constitutes part of the application. Please refer to the Protocol Development station for details of protocol content.
The final protocol should be signed off by the Chief Investigator as a minimum, but usually other signatures may be required such as those from the sponsor and trial statistician. The sponsor should specify (usually in their policies/procedures) which signatures are required and the Chief Investigator should be aware of their local requirements.
In multi-site trials, it is good practice to ensure the Principal Investigator signs a protocol signature page to confirm receipt and also their agreement to work to the current version of the protocol.
In addition the Funder should be informed of any changes to a protocol and their agreement to these obtained.
Further reading:
• Gamble et al. (2017) recommend a minimum set of items that should be addressed and included in Statistical Analysis Plans for clinical trials.
The following checklist for Chief Investigators has been designed as a means of checking that the necessary documentation required for the permissions and approvals process are in place.
Chief Investigator Checklist (before seeking approvals)
• Sponsor(s) identified and agreements for allocation / delegation of responsibilities (if necessary) are in place
• Arrangements for appropriate Patient and Public Involvement
• Input from a statistician secured
• Peer review complete
• Arrangements for a data monitoring committee, steering group and/or management group in place (with consent from members)
• Trial risk assessment carried out, trial management systems and monitoring plan/arrangements in place
• Funding secured
• Unique trial number and EudraCT number obtained
• R&D and local NHS support departments (e.g. pharmacy, labs, radiology etc) consulted and capacity available
• Contracts and agreements in place including third party agreements where outsourcing of any trial specific test/services is required
• Insurance and indemnity arrangements in place (non NHS)
• CVs of investigators (signed and dated)
• Arrangements for trial supplies in place
• Arrangements for pharmacovigilance considered
• Systems in place to ensure trial will be conducted to the principles of GCP and Clinical Trials Regulations
• Trial Master File established
• Protocol and associated documents (see relevant stations):
o EudraCT number on all documentation
o End of trial defined
o Safety reporting section of the protocol outlining definitions and reporting requirements
o All written information provided to/viewed by subjects (e.g. Participant information sheets, consent forms, patient diaries, recruitment advertisements) finalised and version controlled
o All other relevant trial documentation finalised and version controlled e.g. questionnaires, case report forms, trial specific SOPs
o Investigator’s brochure or SmPC developed/identified.
The Integrated Research Application System (IRAS) is a single system for applying for the permissions and approvals for health and social / community care research in the UK. This includes applications for Ethics Approval, Clinical Trial Authorisation and NHS Permission (R&D Management approval). In addition IRAS can be used to create ‘Notice of Substantial Amendment’ forms (see Substantial Amendment station).
IRAS can be used by anyone carrying out health and social / community care research in the UK, including all Chief Investigators and those with delegated responsibility for applying for research approvals and permissions.
Users of the system must have an IRAS account. On-screen instructions provide guidance on opening an IRAS account.
IRAS provides extensive guidance in the Help section and via Question Specific Guidance that can be accessed as the form is completed by clicking the green “i” buttons. IRAS also provides an e-learning module that is free to use and does not require registration. This module provides a simple overview of the system and its functionality.
Careful and considered completion of the project filter is essential as this will determine which permissions and approvals
applications are created for the project and which questions are enabled and disabled. Questions that are not relevant to the type of project will be disabled in the project dataset. For example, indicating that participants will have exposure to ionising radiation would enable a group of questions in the project dataset about ionising radiation and additional declaration for Medical Physics Experts and Clinical Radiation Experts. It is important to be aware that the project filter is dynamic and so further questions may be enabled in the filter depending on the selections made.
It is suggested that all questions are completed in the ‘Full Set of Project Data’ (integrated dataset for all project forms) as this is the most effective way of populating all individual application forms. Not all questions are required in each form, so populating from individual forms will not guarantee that all required sections in other forms are completed. Please see Guidance for new and first time users of IRAS for further information.
Further reading:
• R&D Consultation station
• CTA Submission station
• Ethics Submission station
• R&D Submission station.
The Integrated Research Application System (IRAS) is a single system for applying for the permissions and approvals for health and social / community care research in the UK. This includes applications for Ethics Approval, Clinical Trial Authorisation and NHS Permission (R&D Management approval). In addition IRAS can be used to create ‘Notice of Substantial Amendment’ forms (see Substantial Amendment station).
IRAS can be used by anyone carrying out health and social / community care research in the UK, including all Chief Investigators and those with delegated responsibility for applying for research approvals and permissions.
Users of the system must have an IRAS account. On-screen instructions provide guidance on opening an IRAS account.
IRAS provides extensive guidance in the Help section and via Question Specific Guidance that can be accessed as the form is completed by clicking the green “i” buttons. IRAS also provides an e-learning module that is free to use and does not require registration. This module provides a simple overview of the system and its functionality.
Careful and considered completion of the project filter is essential as this will determine which permissions and approvals applications are created for the project and which questions are enabled and disabled. Questions that are not relevant to the type of project will be disabled in the project dataset. For example, indicating that participants will have exposure to ionising radiation would enable a group of questions in the project dataset about ionising radiation and additional declaration for Medical Physics Experts and Clinical Radiation Experts. It is important to be aware that the project filter is dynamic and so further questions may be enabled in the filter depending on the selections made.
It is suggested that all questions are completed in the ‘Full Set of Project Data’ (integrated dataset for all project forms) as this is the most effective way of populating all individual application forms. Not all questions are required in each form, so populating from individual forms will not guarantee that all required sections in other forms are completed. Please see Guidance for new and first time users of IRAS for further information.
Further reading:
• R&D Consultation station
• CTA Submission station
• Ethics Submission station
• R&D Submission station.
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 (PDF, 878 KB).
Prior to submission to the MHRA, each trial must be registered on the European Clinical Trials Database by obtaining a EudraCT number (see station). A fee is also payable to the MHRA (see fees section of the MHRA website).
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) (also see IRAS station) 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.
Pilot to test a combined MHRA-REC approval process:
The HRA and MHRA are exploring ways to streamline approval and ongoing management of CTIMPs through a combined ways of working pilot. The pilot brings together the two organisations’ regulatory approvals, streamlining the process in a way that would fit with the EU’s new Clinical Trial Regulation.
The pilot process requires a single CTIMP application to be submitted for both the CTA and the REC opinion. Applicants then receive a combined communication to request any further information required and a single communication to confirm the final decision.
The CTA Application Flowchart (pdf, 11.82 KB) gives an overview of the application process.
For non-CTIMP research, a Clinical Trials Authorisation is not required.
Further reading:
• Permissions & Approvals Obtained station.
Application for Ethical Review:
The Health Research Authority (HRA) facilitates ethical research that is of potential benefit to participants. The Research Ethics Service (RES) is a core function of the HRA. Whilst the majority of research conducted within the NHS requires ethical review, there are some important exceptions that can be identified by using the HRA Decision Tool.
Since March 2016, HRA Approval has been the process for applying for approvals for all project-based research in the NHS led from England. In April 2018 this has been extended to include all project-based research in the NHS in Wales, and HRA Approval is now referred to as ‘HRA and HCRW Approval’. Scotland and Northern Ireland have their own systems for ethics approval.
In the UK, applications should be made using the Integrated Research Application System (IRAS) (see also IRAS station for more information).
Patient and Public Involvement (PPI):
Ethics Committees will consider researcher’s plans for PPI as part of the ethical review process. N.B. 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:
Applications for ethical approval of a gene therapy clinical trial must be made to the Gene Therapy Advisory Committee (GTAC) which is the national REC for gene therapy clinical research according to regulation 14(5) of The Medicines for Human Use (Clinical Trials) Regulations 2004. Details of the application process can be found on the HRA pages for the Gene Therapy Advisory Committee.
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.
*Experimental medicine is defined as ‘Investigations undertaken in humans, relating where appropriate to model systems, to identify mechanisms of pathophysiology or disease, or to demonstrate proof-of-concept evidence of the validity and importance of new discoveries or treatments.’
Research summaries:
Since 2014, the HRA have been publishing research summaries of all new research approved by a NHS REC, usually within 90 days of the REC opinion. Further information can be found on the HRA web pages.
Further reading:
• HRA: Research Ethics Service (RES).
Clinical trials conducted on the premises of an NHS organisation, with NHS patients or with NHS staff, require permission from the local NHS R&D office. Coordinated systems for NHS R&D review are in place across the UK. The system available will depend on where the lead NHS R&D office is based (the part of the UK where the Chief Investigator is located).
1. Since March 2016, HRA Approval has been the process for applying for approvals for all project-based research in the NHS led from England. In April 2018 this has been extended to include all project-based research in the NHS in Wales, and HRA Approval is now referred to as ‘HRA and HCRW Approval’. The HRA Web Pages contain detailed guidance on the application process and the HCRW website contains further information relating to site set up in Wales.
2. Researchers wishing to conduct research in the NHS in Scotland (or Health and Social Care (HSC) in Northern Ireland) must obtain ‘NHS (or HSC) management permission’ (also referred to as ‘R&D approval’ or ‘R&D permission’) for each NHS/HSC research site.
Further information on cross-border research within the UK can be found on the Four Nations NHS/HSC Compatibility Programme.
The Integrated Research Application System (IRAS) provides guidance on the completion and submission of applications to all countries in the UK.
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. In addition, the investigator should be aware of any local policies relating to the gaining approval from their non-NHS sponsor/host organisation and requirements for non-NHS SSI Forms to be provided to the REC.
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 have produced PIC guidance and IRAS provides guidance on the arrangements for setting up PICs via the system that is in operation in the part of the UK where the PIC is based.
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 trial cannot begin until all the relevant permissions and approvals have been obtained and reviewed by the relevant parties (including the funder where appropriate).
Clear evidence of the documents submitted to the approval bodies (the submission package) and the documents that were approved (approval letters referencing the submission package*) need to be retained in the Trial Master File. This will allow auditors / inspectors to confirm that all legal and good practice requirements have been followed.
*For Type A clinical trial (See Risk Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products (PDF, 247 KB)), the MHRA may not send the sponsor a formal approval letter. The acknowledgement letter, confirming the trial can go ahead if no objections are raised within 14 days of the application, will act as the authorisation.
Further reading:
• IRAS station
• CTA Submission station
• Ethics Submission station
• R&D Submission station
• Final Trial Management Documentation station.
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.
Final Documentation Checklist
The following list is a suggested guide for Chief Investigators relating to documentation that should be in place at the main site before a trial begins. This list is not exhaustive and local documents may also be applicable.
• Confirmation of Sponsorship letter
• Final approved trial protocol signed by all parties according to local requirements
• Transparency information relating to the processing of personal data under GDPR in accordance with sponsor/HRA Guidance
• Final approved participant information sheet(s) and consent form(s) and GP letter
• Final approved other written participant information e.g. diary card(s)
• Final approved participant recruitment advertisement (if relevant)
• Research ethics committee (REC) approval
• NHS Permission/HRA Approval
• Clinical Trial Authorisation (CTA)* with any stated conditions addressed (if appropriate)
• Final approved risk assessment document and any monitoring plan
• Sign off from a statistician (if required)
• Signed off/finalised case report forms (CRFs)
• Signed off/finalised clinical database (if required by local policy)
• Systems for managing safety data (e.g. in pharmacovigilance database) agreed and finalised
• Details of any data monitoring committee or trial steering or management group (if not in protocol)
• Access to all relevant standard operating procedures (SOPs)
• Investigator’s Brochure or Summary of Product Characteristics
• Signed agreements including operational and financial arrangements
• Statement of insurance to document compensation to participants for trial-related injury (non NHS)
• CVs and other evidence of relevant training (e.g. GCP/Regulation/protocol) and qualifications for the investigator(s) and local study team members
• Normal values/ranges for laboratory/medical/technical tests/procedures
• Laboratory accreditation(s)
• Pharmacy documentation/file
• Decoding procedures for blinded trials
• All records for Investigational Medicinal Products(s) procurement/supply (e.g. shipping)
• Template logs including delegation logs, screening/enrolment logs, participant identification log, randomisation logs (where applicable)
• Trial start-up/initiation report or confirmation that site initiation activities have been completed.
In addition please refer to relevant stations for more information.
During the review process, regulatory and governance bodies may request alterations to trial documentation before final approval is given. The Chief Investigator should ensure that once the approval process is complete, the same version of each document has been approved by all relevant bodies (e.g. MHRA, REC and NHS R&D offices).
* Clinical trials that qualify for the MHRA notification scheme do not require a CTA if the submission has been acknowledged as valid and 14 days have elapsed since then. In this instance, the acknowledgement letter will act as authorisation.
Further reading:
• EMA Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials (2017).
The trial is generally considered to have ‘commenced’ when any of the trial procedures (such as patient screening/consent) that are set out in the protocol, are initiated*.
In the UK, if the sponsor decides to abandon the trial before it commences, the Chief Investigator or sponsor should notify the ethics committee by letter, giving reasons. Details of the notification process to the MHRA (initial e-mail followed by letter) can be found on the ‘Withdrawal of a Clinical Trial Authorisation’ pages of the MHRA website. Other bodies, such as local NHS R&D Offices and funders will also require notification.
*Please note that a trial funder may have a different view on when a trial ‘commences’ e.g. when payments are released, and this can be several months before any consent or screening processes are undertaken. A funder should be kept informed aof all developments and will advise on appropriate processes and requirements.
Further reading:
• Temporary Halt or Early Termination of a Trial station – outlines the requirements for halting/terminating a trial once it has commenced.
Once all of the relevant approvals are in place, all documentation has been finalised, and all participating sites have the information they need, the trial can begin.
This process is often achieved by a holding start-up meeting at each site (site visit or teleconference). The Chief Investigator is then able to satisfy him/herself that all technical aspects of a trial and protocol requirements are fully understood by all relevant site staff. Trial specific training (protocol and trial-specific procedures) as well as training on aspects of trial conduct such as Case Report Form (CRF) completion and safety reporting requirements is often undertaken at this stage. The site also has an opportunity to ask questions and clarify misunderstandings.
For Clinical Trials of Investigational Medicinal Products (CTIMPs), this communication should also include pharmacy (where applicable) so that they can confirm that all requirements are in place before dispensing Investigational Medicinal Products (IMPs) to subjects (see Trial Supplies station).
Generally, there is an expectation that a trial should start (recruitment activities) within a specified time period. For example, the ethics committee will assume that the research will commence within 12 months of the date of favourable ethical opinion and may review its opinion if the trial does not start with 24 months of receipt of the final opinion letter.
The NIHR Research Support Services Framework has been developed to assist providers of NHS research in starting research more efficiently. The NIHR publish metrics to measure efficiencies which include trial initiation time. A benchmark of 70 days for trial initiation begins with receipt of a valid research application. Guidance on interpretation of the definition of receipt of valid research application has been produced by the NIHR.
Subjects must give their informed consent before being entered into a trial*. Consent should be obtained before the first trial-specific activity is undertaken. For Clinical Trials of Investigational Medicinal Products (CTIMPs), Schedule 1 of The Medicines for Human Use (Clinical Trials) Regulations 2004 describes the requirements for consent.
*With the exception of certain emergency trials involving vulnerable subjects (minors or incapacitated adults – please see below).
For each trial, specific consent documentation consisting of a participant information sheet and consent form must be developed and approved by the ethics committee. The HRA consent web pages contain a range of documents including guidance and templates for preparing the consent documentation. It should be noted that involvement of patient groups when developing the consent process/documentation is looked upon favourably by ethics committees (see HRA Consent and Participant Information Sheet Preparation Guidance).
Throughout the trial, the subject’s willingness to continue participation should be reaffirmed periodically. However, if significant new information becomes available, subjects are provided with revised (and re-approved) consent documentation so that written consent can be formally documented if the subject is willing to continue.
For CTIMPs in Scotland, the legal provisions for incapacitated adults are slightly different. The legal representative will be the person who is able to consent to treatment under Section 51 of the Adults with Incapacity (Scotland) Act 2000 and as detailed in Part 1, 2(b) of Schedule 1. In Northern Ireland, it is currently governed by common law.
**A legal representative would only give consent on behalf of a minor in the rare circumstance that a person with parental responsibility is not available prior to their proposed inclusion by reason of the emergency nature of the treatment.
Informed Consent in Clinical Trials published by the HRA, outlines the hierarchy for consent using personal or professionallegal representatives. This document also describes the changes brought about by SI 2008 941 and SI 2006 2984 which amended provisions for consent in the emergency setting for minors (see section 16) and for incapacitated adults (see section 21).
For CTIMPs in Scotland, the legal provisions for incapacitated adults are slightly different. The legal representative will be the person who is able to consent to treatment under the Adults with Incapacity (Scotland) Act 2000 and as detailed in Part 1, 2(b) of Schedule 1.
Research other than CTIMPs:
In England and Wales, it is the Mental Capacity Act that regulates inclusion into research. Separate guidance is available from the HRA Consent Web Pages.
Access of Patient Information for Research Without Consent
In certain research studies, there may be sufficient justification to access confidential patient information without consent. Section 251 of the NHS Act 2006 allows the Secretary of State for Health to make regulations to set aside the common law duty of confidentiality for defined medical purposes. The HRA took on responsibility for Section 251 and has established the Confidentiality Advisory Group (CAG).
The MRC Data and Tissue Toolkit provide further guidance on aspects of consent for the use of data and tissue in research.
General Data Protection Regulations (GDPR)
The GDPR requires organisations to publish transparency information when processing personal data for health and care research. Suitable transparency wording for public sector sponsors to use in participant information sheets can be accessed from the HRA website, along with comprehensive guidance.
Consent methods in paediatric emergency and urgent care trials
The CONNECT guidance was developed for all those who have a direct or indirect role in the funding, design, conduct and ethical review of paediatric or neonatal trials that involve critically ill children.
Clinical research involving children is essential to improve healthcare for children, yet there is evidence that health professions often feel uneasy about asking children and their families to take part in clinical trials. This brief guidance and further resources from the Nuffield Council on Bioethics can help researchers when seeking consent for children’s participation in clinical research
The MRC Hubs for Trial Methodology Research
The MRC HTMR have a number of other resources relevant to consent:
The Quintet Recruitment Intervention (QRI) aims to facilitate informed decision making by patients about RCT participation
This review provides an introduction to qualitative research techniques and explains how this approach can be used to understand, and subsequently improve, recruitment and informed consent within a range of clinical trials.
This paper describes three key techniques that recruiters can use to address patients’ treatment preferences to facilitate recruitment and informed consent.
Clinicians’ personal views about trial treatments can encroach on their ability to convey equipoise to patients. This article identifies broad practices that support or hinder equipoise communication.
The DevPICv2 provides a measure of informed consent that can be applied directly to recruitment appointments where trial participation is discussed in order to evaluate the quality of recruiter information provision and evidence of patient understanding.
The Q-QAT (Quanti-Qualitative Appointment Timing) is a simple technique to systematically identify key challenges to recruitment that stem from how the RCT and treatments are portrayed to patients in recruitment appointments. It can be used as a stand-alone intervention to assist in understanding RCT recruitment or as part of the development of strategies to improvement recruitment and informed consent.
Further reading:
• ICH GCP (E6) R2: (Section 4.8) Informed Consent of Trial Subject.
• The Clinical Trials Transformation Initiative (CTTI), a US public-private partnership, has produced guidance and tools relating to informed consent.
• MRC: Guidance on patient consent (including research involving children and adults who lack capacity).
• GMC: Consent to Research.
• INVOLVE: Public Involvement in Research: Impact on Ethical Aspects of Research (PDF, 528 KB).
• WMA: Declaration of Helsinki.
Safety Reporting
The sponsor is responsible for the on-going safety evaluation of the Investigational Medicinal Product(s) used in a Clinical Trial of Investigational Medicinal Products (CTIMPs).
Part 5 of the Medicines for Human Use (Clinical Trials) Regulations SI 1031 (sections 32-35) define the responsibilities for safety reporting of both the sponsor and the investigational site.
Details of how to send safety reports to the ethics committee are provided on the HRA web pages.
The sponsor should develop formal, written processes for the management of adverse events and safety reports including the handling of both (1) expedited and (2) annual safety reporting:
1. A flowchart (pdf, 129.26 KB) has been developed giving an overview of the expedited safety reporting requirements for a UK open label trial.
2. The annual safety report for CTIMPs should be in the format of a Development Safety Update Report (DSUR) set out in the ICH E2F guideline. Any researcher who has been assigned the task of completing a DSUR should also follow their local policies/procedures.
Comprehensive guidance on the production of the DSUR and other safety reporting requirements can be found in the Joint Project Workstream Document: Pharmacovigilance (pdf, 344.05 KB). The Principal Investigator should make all investigational site staff aware of the trial’s safety reporting requirements and have systems to ensure all relevant events are detected, recorded and notified in accordance with the protocol and Clinical Trials Regulations.
Investigator responsibilities for safety reporting are outlined the Joint Project Workstream Document: Pharmacovigilance (pdf, 344.05 KB) – section 4.
For non-CTIMP research, safety reporting requirements are described on the HRA web pages.
Further reading:
• Pharmacovigilance station.
There is a requirement to send progress reports to a number of interested parties throughout a trial. For example, Trial Steering Committees and Funders will require regular updates and routine reports.
Trial initiation performance must be reported by NHS providers, when subject to an NIHR contract. The benchmark for trial initiation is a 70 day period which begins on receipt of a valid research application. The NIHR provides a definition of receipt of valid research application.
An annual progress report is also sent to the ethics committee. The HRA website provides a specific Annual Progress Report Template for CTIMPs relating to completion and submission of this report. In addition, progress reports are usually required by the trial sponsor and the NHS R&D Office(s) where the trial is conducted.
