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Research For You

Improving quality of life.

MAC Clinical Research is the UK’s leading clinical trials organisation. As an award winning healthcare organisation, we are dedicated to developing new and improved treatments for a range of medical conditions.

Every year across the UK thousands of people take part in medical trials. Volunteers, just like you, play a significant role in helping to find tomorrow’s breakthrough medications. Without these participants there would be no advances in treatment options.

By taking part in a clinical trial with MAC you can make a real difference, and you can benefit in many different ways.

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Clinical trials

A clinical trial compares the effects of 1 treatment with another. It may involve patients, healthy people, or both.

How do I take part in a clinical trial?

You can ask your doctor or a patient organisation if they know of any clinical trials that you may be eligible to join.

You can also search for information on a number of websites and register your interest in taking part in research.

Be Part of Research website

The  Be Part of Research website has information about clinical trials and other research from several different UK registers.

You can also search the Be Part of Research site to find trials relevant to you, and you can contact researchers yourself.

World Health Organization (WHO) International Clinical Trials

The  WHO International Clinical Trials Registry Platform (ICTRP) website provides access to clinical trials in countries all around the world.

For some health conditions, you can find out about clinical trials from the websites of charities.

Examples are:

• Versus Arthritis: Our current research
• Cancer Research UK: Find a clinical trial
• Multiple Sclerosis Society: Be in a study
• Target Ovarian Cancer: Clinical trials
• Parkinson's UK: Take part in research
• Blood Cancer UK: Clinical trials information hub
• Alzheimer's Research UK: Getting involved in research

Why join a clinical trial?

Clinical trials help doctors understand how to treat a particular illness. It may benefit you, or others like you, in the future.

If you take part in a clinical trial, you may be one of the first people to benefit from a new treatment.

But there's also a chance that the new treatment turns out to be no better, or worse, than the standard treatment.

To hear other people's experiences of taking part in a clinical trial, visit the healthtalk.org website

Will I get paid?

Some clinical trials offer payment, which can vary depending on what's involved and expected from you.

Some trials do not offer payment and just cover your travel expenses.

It's important to find out about the inconvenience and risks involved before you sign up, and to carefully weigh up whether it's worth it.

Bear in mind:

• it can be time consuming – you may be expected to attend a number of screening and follow-up sessions, and some trials require you to stay overnight
• there may be restrictions on what you can and cannot do – for example, you may be asked to not eat, or not drink alcohol, for a period of time
• you may experience unknown side effects from the treatment

What happens in a clinical trial?

Testing a new medicine.

All clinical trials of new medicines go through a series of phases to test whether they're safe and whether they work.

The medicines will usually be tested against another treatment called a control.

This will either be a dummy treatment (a placebo) or a standard treatment already in use.

Phase 1 trials:

• A small number of people, who may be healthy volunteers, are given the medicine.
• The drug is being trialled in human volunteers for the first time.
• Researchers test for side effects and calculate what the right dose might be to use in treatment.
• Researchers start with small doses and only increase the dose if the volunteers do not experience any side effects, or if they only experience minor side effects.

Phase 2 trials:

• The new medicine is tested on a larger group of people who are ill. This is to get a better idea of its effects in the short term.

Phase 3 trials:

• Carried out on medicines that have passed phases 1 and 2.
• The medicine is tested in larger groups of people who are ill, and compared against an existing treatment or a placebo to see if it's better in practice and if it has important side effects.
• Trials often last a year or more and involve several thousand patients.

Phase 4 trials:

• The safety, side effects and effectiveness of the medicine continue to be studied while it's being used in practice.
• Not required for every medicine.
• Only carried out on medicines that have passed all the previous stages and have been given marketing licences – a licence means the medicine is available on prescription.

Control groups, randomisation and blinding

If you take part in a clinical trial, you'll usually be randomly assigned to either the:

• treatment group – where you'll be given the treatment being assessed, or
• control group – where you'll be given an existing standard treatment, or a placebo if no proven standard treatment exists

While the treatments are different in the 2 groups, researchers try to keep as many of the other conditions the same as possible.

For example, both groups should have people of a similar age, with a similar proportion of men and women, who are in similar overall health.

In most trials, a computer will be used to randomly decide which group each patient will be allocated to.

Many trials are set up so nobody knows who's been allocated to receive which treatment.

This is known as blinding, and it helps reduce the effects of bias when comparing the outcomes of the treatments.

What should I know before I sign up?

When you express interest in a trial, a doctor or nurse is likely to tell you something about it in person.

You'll also be given some printed information to take away.

You may come back with some questions you feel have not been answered.

General questions

• What's the aim of the trial and how will it help people?
• Who's funding the trial?
• What treatment will I get if I do not take part in the trial?
• How long is the trial expected to last, and how long will I have to take part?
• How long will it be before the results of the trial are known?
• What will happen if I stop the trial treatment or leave the trial before it ends?
• What would happen if something went wrong? It's rare for patients to be harmed by trial treatments, but you may want to ask about compensation if this were to happen.

Practical questions

• How much of my time will be needed?
• Will I need to take time off work?
• Will I be paid?
• Will the costs of my travel to take part in the trial be covered?
• If the trial is testing a new drug, will I have to collect it from the hospital, will it be sent to me by post, or will I get it through my doctor?
• Will I have to complete questionnaires or keep a diary?
• What are the possible side effects of my treatment?
• How could the treatments affect me physically and emotionally?
• Who can I contact if I have a problem?
• Will someone be available 24 hours a day?
• How do I find out the results of the trial?

Things to weigh up

As with any treatment, you cannot be sure of the outcome.

You may be given a new treatment that turns out not to be as effective as the standard treatment.

Also, it's possible you'll experience unexpected side effects.

And bear in mind that you may have to visit your place of treatment more often, or have more tests, treatments or monitoring, than you would if you were receiving the standard treatment in usual care.

Leaving a trial

You may decide to stop taking part in a trial if your condition is getting worse or you feel the treatment is not helping you.

You can also choose to leave at any point without giving a reason and without it affecting the care you receive.

At the end of the trial, the researchers should publish the results and make them available to anyone who took part and wanted to know the results.

If the researchers do not offer you the results and you want to know, ask for them.

Some research funders, such as the National Institute for Health Research (NIHR), have websites where they publish the results of the research they have supported.

Visit the NIHR website to find out more

How are trials regulated and judged ethical?

Before a clinical trial of a new medicine can begin, a government agency called the Medicines and Healthcare products Regulatory Agency (MHRA) needs to review and authorise it.

The MHRA also inspects sites where trials take place to make sure they're conducted in line with good clinical practice.

Visit the GOV.UK website to read about the MHRA

The Health Research Authority (HRA) works to protect and promote the interests of patients and the public in health research. 

It's responsible for research ethics committees up and down the country.

All medical research involving people in the UK, whether in the NHS or the private sector, first has to be approved by an independent research ethics committee.

The committee protects the rights and interests of the people who will be in the trial.

Find out more on the HRA website

How are trial results used to improve treatment?

Clinical trials can help:

• prevent illnesses by testing a vaccine
• detect or diagnose illnesses by testing a scan or blood test
• treat illnesses by testing new or existing medicines
• find out how people can control their symptoms or improve their quality of life – for example, by testing how a particular diet affects an illness

Many clinical trials are designed to show whether new medicines work as expected.

These results are sent to the MHRA, which decides whether to allow the company making the medicine to market it for a particular use.

Licensing a treatment

If research has identified a new medicine, the MHRA must license it before it can be marketed.

Licensing shows a treatment has met certain standards of safety and effectiveness.

Safety must be monitored carefully over the first few years of a newly licensed treatment.

This is because rare side effects that were not obvious in clinical trials may show up for the first time.

In England and Wales, the National Institute for Health and Care Excellence (NICE) decides whether the NHS should provide treatments.

Find out more on the NICE website

Where can I find results from trials that are relevant to me?

The results of clinical trials are usually published in specialist medical journals and online libraries of evidence.

Some of the most well-known examples are:

• The Lancet  medical journal
• British Medical Journal (BMJ)
• The New England Journal of Medicine
• Cochrane Library  – a collection of high-quality evidence

You can use a search engine such as Google to look for articles and read summaries (abstracts).

But you cannot usually see the full articles without a subscription to the journal.

Also, research papers are not written in plain English and often use many medical, scientific and statistical terms. They can be very difficult to understand.

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Welcome to the UK Clinical Research Collaboration

Strengthening experimental medicine.

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The UK Clinical Research Collaboration (UKCRC) Partners' goal is to establish the UK as a world leader in clinical research. The UKCRC provides a forum that enables all Partners to work together to transform the clinical research environment in the UK.

The forum promotes a strategic approach to the identification of opportunities and obstacles to clinical research and their resolution. In so doing the UKCRC aims to benefit the public and patients by improving national health and increasing national wealth.

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• Health and social care
• Research and innovation in health and social care

The Future of UK Clinical Research Delivery: 2021 to 2022 implementation plan

• Department of Health & Social Care
• Northern Ireland Executive
• Scottish Government
• Welsh Government

Published 23 June 2021

© Crown copyright 2021

This publication is licensed under the terms of the Open Government Licence v3.0 except where otherwise stated. To view this licence, visit nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] .

Where we have identified any third party copyright information you will need to obtain permission from the copyright holders concerned.

This publication is available at https://www.gov.uk/government/publications/the-future-of-uk-clinical-research-delivery-2021-to-2022-implementation-plan/the-future-of-uk-clinical-research-delivery-2021-to-2022-implementation-plan

Ministerial foreword

Earlier this year we, the UK government and devolved administrations, set out our bold and ambitious vision for the future of clinical research delivery. As we continue to emerge from the shadow of the pandemic, Saving and Improving Lives: The Future of UK Clinical Research Delivery lays out our ambition to create a world-leading UK clinical research environment which is more efficient, more effective and more resilient, with research delivery embedded across the NHS.

By delivering on this vision, we will turn the promise of cutting-edge UK science, from genomics to novel cancer vaccines, into real improvements in disease prevention, diagnosis and treatment. This means better healthcare and better outcomes for all patients, both at home and around the world.

Today we publish our plan for 2021 to 2022, which is our launchpad to propel UK clinical research into the future. Here we detail the tangible steps we will take in the coming months, with UK-wide cross-sector partnership, to begin to turn our vision into reality. With the right investment in place, we will publish further plans in the coming years, which will build upon these strong foundations to create a fully digitally enabled, pro-innovation and patient-centred research environment.

Our plan reflects the close collaboration that makes the UK clinical research environment so strong. Delivery will be overseen by the UK-wide Clinical Research, Recovery, Resilience and Growth ( RRG ) programme, which brings together:

• partners from across industry
• universities
• medical research charities

By bringing everyone together under this plan and the banner of the RRG programme, we can drive the managed recovery of non-COVID research, continue to deliver on existing commitments to improve research delivery and begin to go even further to tackle long-term barriers and embed sustainable, effective and innovative new practices across our sector.

From expediting ethical approval and study set-up, to fresh investment to digitise clinical research delivery, this plan will increase the UK’s capacity and capability to deliver cutting-edge clinical research. As a result, we will bring more research and greater investment to our shores, bolstering our economic growth, tackling health inequalities and improving the health of people right across the UK.

Importantly, our plan is part of a wider government drive to support clinical research and life sciences. We are building upon existing commitments and priorities set out in the NHS Long Term Plan , the Life Science Sector Deals , A Healthier Wales and the framework for NHS Scotland .

We are aligning our plans for clinical research with wider government strategies to ensure the UK is at the forefront of health innovation, from the UK Rare Diseases Framework to the Genome UK Strategy , which sets out how we will extend the UK’s leadership in genomic healthcare and research.

By breaking down barriers to support research across the UK our plan will complement other initiatives to unlock the power of data to drive research. This includes those set out in the UK’s National Data Strategy ( NDS ) published in September 2020, the recently published draft Data Strategy for Health and Social Care for England and equivalent initiatives in the devolved administrations, such as a further iteration of Scotland’s health and social care data strategy.

Taking these first steps in delivering our plan will need the ongoing participation of everyone across the sector. By working together, we can begin to turn our vision into a reality – creating a clinical research ecosystem which capitalises on innovation, is resilient in the face of future healthcare crises and offers fresh hope for patients right across the country.

That is what the people of this United Kingdom deserve and what the UK government and devolved administrations will deliver.

Lord Bethell of Romford Parliamentary Under Secretary of State for Innovation Department of Health and Social Care

Robin Swann Minister for Health Northern Ireland Executive

Eluned Morgan Minister for Health and Social Services Welsh Government

Humza Yousaf Cabinet Secretary for Health and Social Care Scottish Government

Executive summary

In March 2021, we published our bold and ambitious vision for The Future of UK Clinical Research Delivery . By working in partnership across the NHS, [footnote 1] regulators, industry, medical research charities, academia and government, we can create a clinical research ecosystem which is more efficient, more resilient and more effective than ever before.

Our vision is underpinned by 5 key themes:

streamlined, efficient and innovative research – so the UK is seen as one of the best places in the world to conduct fast, efficient and cutting-edge clinical research

clinical research embedded in the NHS – to create a research-positive culture in which all health and care staff feel empowered to support and participate in clinical research as part of their job

patient-centred research – to make access to, and participation in, research as easy as possible for everyone across the UK, including rural, diverse and under-served populations

research enabled by data and digital tools – to ensure the UK has the most advanced and data-enabled clinical research environment in the world, which capitalises on our unique data assets to improve the health and care of patients across the UK and beyond

a sustainable and supported research workforce – which offers rewarding opportunities and exciting careers for all healthcare and research staff of all professional backgrounds – across the length and breadth of commercial and non-commercial research.

This plan is our first step in making this vision a reality and will serve as a launchpad to propel UK clinical research into the future. Here we lay out the tangible steps we will collectively undertake during the coming months in close collaboration with the clinical research community and our delivery partners through the UK Clinical Research RRG programme.

The RRG programme board brings together delivery partners from across the UK to ensure system leadership, oversight and strategic co-ordination of our work. Partners include:

• UK health departments
• the Office for Life Sciences
• National Institute for Health Research ( NIHR )
• NHS England and NHS Improvement ( NHSEI )
• NHS Digital
• Digital Health and Care Wales ( DHCW )
• Health and Care Research Wales
• NHS Research Scotland ( NRS )
• Health and Social Care Northern Ireland ( HSCNI )
• Health Research Authority ( HRA )
• Medicines and Healthcare Products Regulatory Agency ( MHRA )
• Association of the British Pharmaceutical Industry ( ABPI )
• Association of Medical Research Charities ( AMRC )

By bringing the whole sector together under this plan and the banner of the RRG programme, we have a unique opportunity to tackle long-term barriers to clinical research delivery and to embed sustainable, effective and innovative new practices across our sector. This will increase the UK’s capacity and capability to deliver cutting-edge clinical research, helping to bring more research and greater investment to our shores, bolstering our economic growth and improving the health of people across the whole of the UK.

To support the delivery of this plan, over £64 million in funding has been secured. This demonstrates the UK’s ongoing commitment to saving and improving lives through clinical research and means that we can take the vital first steps towards delivering on our overarching vision.

However, we know we need to go much further. While delivery of our phase 1 plan is underway, we will continue to co-ordinate across the clinical research community to agree areas for further action. With the right investment in place, we will then publish further plans in the coming years, which will build upon the work we set out below to unleash the full potential of UK clinical research, by creating a fully digitally enabled, pro-innovation and patient-centred research ecosystem.

Our key commitments within this plan are to:

deliver our UK-wide programme of work to drive the managed recovery of multi-site studies over the next 12 months. The UK remains highly active in the research and development of novel COVID-19 medicines. However, as the pressures of the pandemic ease, we will manage the recovery of research across all phases, therapy areas and treatment types, with COVID-19 becoming one speciality among a diverse research portfolio. Working with commercial and non-commercial funders, NIHR on behalf of the UK, will sequence the rapid recovery of selected studies across a range of conditions and ensure the UK is able to deliver the levels of activity needed to contribute to global studies

continue delivery of existing commitments to make UK clinical research delivery easier, more efficient and more effective. We will offer an option of HRA Rapid Research Ethics Committee review as part of the roll-out of the UK Research Ethics Committee and MHRA combined review of clinical trials of medicines. This will build upon the use of the Integrated Research Application System ( IRAS ) as the new digital portal for research approvals and study set-up across the UK. In addition, we will reduce the variation and time spent negotiating costs for commercial research through the National Contract Value Review, which will ensure an aligned process for contracting of research across the whole of the UK

begin to deliver ambitious new initiatives that will set us on the path towards realising our bold vision for the future of UK clinical research. We will take the first steps towards digitising the clinical research process to make it faster and cheaper by beginning to create a holistic, data-enabled find, recruit and follow-up service. Flexible workforce and delivery models will be expanded, including capacity for research in primary and community care, and the package of incentives and metrics used to drive performance across the system will be reviewed and updated. We will also support and enable the delivery and evaluation of innovative models of trial delivery, such as hub-and-spoke, decentralised models and remote participation

Given the scope of the work and the fast pace of change in clinical research, we will keep the specifics of this plan under review via the RRG programme and we will adapt delivery as needed to ensure we meet any new challenges as they arise. The RRG programme will also hold responsibility for the monitoring and evaluation of delivery, to ensure that progress against our commitments is measured and assessed.

By delivering on this plan, we will take our first firm steps towards achieving our overarching vision – to make the UK one of the most attractive places in the world to conduct efficient and cutting-edge clinical research that unlocks the power of new treatments and technologies to revolutionise patient care.

We recognise that health policy is a devolved responsibility, where the UK and devolved administrations have distinct ownership over implementation. However, while there are different approaches to the delivery of clinical research across the UK, we are committed to delivering on a vision with a UK-wide reach and in pursuit of a common goal – to create a seamless and interoperable service across the UK to support clinical research delivery, shaping the future of healthcare and improving people’s lives.

We are therefore creating a joined-up system – where sponsors of both commercial and non-commercial research can easily deliver studies across the UK and patients anywhere in the country can easily participate.

To ensure compatible and consistent ways of working across England, Scotland, Wales and Northern Ireland many commitments in this plan are focused on UK-wide implementation. Organisations such as MHRA and HRA have a UK-wide reach and as such their actions will have impacts across the UK. In other instances, actions are being led by a specific organisation on behalf of the UK, while other actions will be delivered through UK partnerships – recognising the different legislative and delivery contexts across the UK government and devolved administrations.

We will continue this collaborative working as part of the RRG programme, to ensure the UK research offer remains co-ordinated and all parts of the country benefit from implementation.

Scotland recognises the strength in ensuring that the UK is a cohesive and streamlined place to undertake clinical research in a global economy. We are committed to improving cross border working, ensuring compatibility and efficiency of clinical research across the UK, and in maintaining and developing our ability to attract research to Scotland and the UK.

Healthcare in Scotland is devolved to the Scottish Government. Fourteen unitary territorial health boards have overall responsibility for delivering service within their geographic area, and these work with a smaller number of special health boards that provide national services. National research support and delivery infrastructure is provided through NHS Research Scotland ( NRS ), embedded within territorial health boards. Study approval and delivery processes are closely aligned through NRS at both national and local levels.

NRS supports clinical research activity through partnership working between the Chief Scientist Office ( CSO ) of the Scottish Government and Scottish Health Boards. NRS works with Scottish Universities and other organisations to ensure that Scotland provides a highly supportive environment for clinical research. NRS is facilitated by a Central Management Team with an established management group and strategic oversight board giving direction and support. In combination this robust governance structure allows the strategic and operational vision to be continually and consistently reviewed, improved and developed with the RRG work being incorporated into these structures.

Clinical Research Facilities ( CRFs ) in the main population centres cover all phases of clinical research. These act as hubs for co-ordination, training and peer support for research support staff to facilitate activity across Scotland – and they will engage with UK-wide activities to support recruitment and delivery, such as the Patient Recruitment Centres in England.

Scotland has a developed health informatics support infrastructure, with core support provided to 4 regional Data Safe Havens supporting regulated and secure access to NHS data. These Safe Havens work in tandem with the national electronic Data Research and Innovation Service (eDRIS) and boards to deliver research and help identify patients to take part in studies. The Scottish Health Research Register ( SHARE ) has consented over 280,000 people to allow their health records to be searched against eligibility criteria to enter research studies. SHARE also provides a mechanism for collection of spare blood collected through routine clinical activities, allowing large-scale, rapid collection for applicable projects. NRS , through the Data Safe Havens and SHARE , continue to develop to facilitate more efficient trial delivery in Scotland. Mechanisms are also being explored to further enhance the use of NHS data to support trials in Scotland and to work with equivalents in supporting UK-wide trials.

Continued engagement in UK-wide activities will strengthen the learning across nations, reducing duplication and increasing deliverability. Participation of NRS in sharing experiences where relevant (for example, in relation to the National Contract Value Review project which mirrors a process already in place in Scotland), and to actively contribute to new developments will ensure compatibility across nations, even where delivery models diverge.

Strong working relationships are in place across the UK, with NRS engaged in work streams detailed within this implementation plan. Further detail around Scottish plans will be published in a Scottish Government Strategy for Health Research, which will encompass plans linked to the RRG work, alongside additional Scotland-specific initiatives.

Wales, through leadership from Health and Care Research Wales, is fully committed to playing its part in delivering a world-leading UK clinical research system. As an active member of the RRG programme, Wales will work collaboratively with all partners to realise our ambitions and improve the health and wellbeing of the population. This vision and plan are aligned to our ‘A Healthier Wales’ strategy, whereby individuals are at the heart of transformation and modernisation of health and care services, and where research is embedded in high quality care.

With the Welsh integrated health board model across primary and community and secondary care, Wales has real opportunities to offer. Working closely in partnership with our NHS leaders, and building on developments that have evolved over the last year, the Wales Study Support Service, which provides a One Wales ‘front door’, will now continue to support co-ordinated set-up, delivery and oversight of clinical research in Wales. In addition, Health and Care Research Wales will provide national co-ordination for the implementation of the actions within this plan, working collaboratively with organisations in Wales and across the UK.

Digital Health Care Wales ( DHCW ) is a new special health authority that was created on 1 April 2021. DHCW will take forward the digital transformations needed for better health and care and lead the delivery of national programmes to establish a modern technology enabled healthcare environment. Building on the existing digital research strengths in Wales (for example, the Secure Anonymised Information Linkage Databank (SAIL)), DHCW will be a pivotal partner in supporting the delivery of this plan through supporting initiatives to make study set-up and delivery faster, more efficient and more innovative.

Health and Care Research Wales will also partner with Health Education and Improvement Wales (HEIW) to realise ambitions in developing and supporting our workforce in Wales, through structured research career pathways and in recognising dedicated time for research for health and care professionals.

New investments have been made in Research, Innovation and Improvement Co-ordination Hubs, focused on driving the adoption and spread of proven innovations and new models of care. In addition, the Intensive Learning Academies are developing management and leadership roles across targeted themes linked to innovation adoption and transformation – with a strong emphasis on ‘case study learning’ that will translate research into better outcomes for patients.

The UK clinical research delivery vision and actions will also be a key feature in the forthcoming Health and Care Research Wales 3-year strategy.

Northern Ireland

Northern Ireland (NI) is committed to full participation in the delivery of the UK-wide vision for the future of clinical research and is already fully involved in many of the UK-wide work streams. Implementation of the vision is a shared goal across the UK, however, with differences in scale or potentially between legislative frameworks, some variations may exist as outlined within this plan. In a number of instances, local solutions have been put in place in Northern Ireland that are compatible with those in other administrations, and aim to provide a seamless experience for those placing research studies at any site across the UK. Northern Ireland recognises the value of a UK-wide approach to clinical research and is working towards collective and compatible solutions in partnership with colleagues.

Health and Social Care in Northern Ireland is delivered by 5 geographical health and social care trusts, the Northern Ireland Ambulance Service, an independent primary care sector and a mixture of statutory and independent care organisations. Delivery of clinical research is undertaken through the Northern Ireland Clinical Research Networks, with 2 clinical research facilities and a single clinical trials unit. Northern Ireland has put in place a Clinical Research Recovery, Resilience and Growth (NI CRRRG) Taskforce to develop a local implementation plan for the delivery of the vision, which will complement this document.

Northern Ireland is yet to implement legislation governing the secondary use of health data. However, this has not prevented Northern Ireland from becoming a full member of the UK Health Data Research Alliance, working towards optimal benefit from shared data across the UK. To date Northern Ireland has expanded their safe haven data access, through the Honest Broker Service, which will soon be offered remotely, in partnership with SAIL in Wales. Northern Ireland is also a partner in the HDRUK core data studies around COVID-19 and is working towards full implementation of secondary uses of data legislation in the coming months, which will provide more scope for participation in the digital actions described in this document. Data will also be a major area of focus for the NI CRRRG Taskforce.

A significant joint investment from Treasury and the Northern Ireland Executive in clinical research is anticipated in Northern Ireland, via regional City Deal initiatives in the 2 main cities, Belfast and Derry. It is expected that the City Deals will bring a collective and collaborative focus on clinical research and digital health, between the 2 universities and Health and Social Care, as well as engaging local industry, driving innovation and attracting significant grant income and inward investment.

In England, we are fully committed to supporting the delivery of this implementation plan, which will provide important foundations for future activities to build towards the delivery of our overarching vision.

As a vital first step towards creating a fully data-enabled clinical research delivery environment, we are beginning to develop a ‘Find, Recruit and Follow-up’ service – to make it easier than ever for researchers to connect with the digital tools and platforms that will expedite research recruitment, set-up and monitoring.

Creating this service will be a major move towards unlocking the power of data to drive research, alongside NHSX’s Health and Social Care Data Strategy and the National Data Strategy ( NDS ), published in September 2020.

Respondents to the NDS consultation confirmed that the framework set out in the NDS is fit for purpose and that government must now take action to ensure that we make the most of data’s many opportunities.

In addition to UK-wide work on managed recovery, NIHR will also take forward further initiatives in England to diversify our research portfolio and increase system capacity. By further bolstering the 5 Patient Recruitment Centres, NIHR will make it easier and more efficient to deliver late-stage commercial research – making the UK more attractive and allowing more people to participate in research that is of relevance to them. NIHR ’s Clinical Research Network ( CRN ) will also expand their existing infrastructure in primary and community care and invest in boosting their research capacity through support for a flexible workforce and the increased use of varied delivery models for innovative research.

NHS England and NHS Improvement ( NHSEI ) will work closely with primary care networks ( PCNs ) and integrated care systems ( ICSs ) to explore how they can be empowered to support research in their local area while sharing best-practice nationally. This collaborative working will ensure the NHS in England can embed research and innovation, both within local communities and on a national scale, to drive improvements in patient care.

The NHS Innovation Service will be established and use ‘demand signalling’ to effectively communicate the needs of the NHS in England. Researchers and innovators will be supported to rapidly research and develop new treatments, technologies and techniques with the potential to address these pressing healthcare challenges, to get proven solutions into the hands of the healthcare staff and patients who need them.

Together these activities in England, complemented by initiatives of the devolved administrations and in conjunction with the UK-wide actions for 2021 to 2022, represent a vital first step to the full realisation and implementation of our vision in future years.

We will pioneer England initiatives while continuing to actively support the wider programme of work that will lay the foundations to create a UK-wide clinical research ecosystem which is more efficient, more effective and more resilient than ever before.

Managed recovery

As we emerge from the shadow of the pandemic and look to the recovery of non-COVID clinical research, we have heard clearly from research funders, sponsors and the NHS that a time-limited managed approach to the recovery of multi-centre studies is essential to our future growth. Stakeholders need increased certainty about when research delivery will restart, so that the UK can continue to make an active and leading contribution to global studies.

The partnerships and collaboration which enabled our success during the pandemic will remain vital as we recover from it. The NIHR CRN , on behalf of the UK, are leading discussions with commercial and non-commercial funders to develop operational plans for a managed recovery of clinical research. This will be undertaken by the Managed Recovery Operations Group and overseen by the RRG programme with input from NHS R&D leaders and a range of wider stakeholders .

This approach will see COVID-19 studies become one speciality among a diverse research portfolio. Targeted support will also enable NHS sites to recover research activity and generate the income needed to maintain and rebuild our expert research delivery workforce, while also supporting research staff as they recover.

To begin to recover research across all phases, therapy areas and treatment types, we commit to support the following actions.

Action area 1: improving the speed and efficiency of study set-up

We know some research in the UK still takes too long to get off the ground. By simplifying and streamlining the route to study set up, incorporating greater transparency and consistency in research approvals and by expediting the processes for costing and contracting, we can reduce these delays and speed up all aspects of study set-up.

Our ambition is that the UK will become the premier destination for streamlined, transparent and efficient research – by removing unwarranted variation and setting up studies in record time. This will bring fresh business and investment to the UK to bolster economic growth and job creation. More importantly, it will set the pace for innovation and ensure research translates into improved patient care.

As our first step to make the UK the best place to deliver innovative, streamlined, effective and efficient research, we commit to support the following actions.

Action area 2: building upon digital platforms to deliver clinical research

We have high-quality data assets and have invested in a range of digital platforms which are already providing valuable services to support research delivery. While the value of these platforms has been demonstrated during COVID-19, the pandemic has also highlighted the need for further development and more cohesion across the data landscape. We now need to increase the scale and interoperability between systems, to support feasibility assessments, improve diverse recruitment and to reduce the burden and costs of clinical research delivery, at both a national and local level. Different legislative frameworks within each UK administration means tailored solutions will be required in each case. However, we are committed to ensuring a seamless and joined up UK-wide approach to research sponsors.

To progress this, in 2021, we are beginning to develop a data enabled ‘Find, Recruit, and Follow-up’ service, to make it easier, faster, and more effective to deliver clinical research. This includes making it easier for researchers to identify and use the most appropriate data and digital tools to deliver their study through study support services. Such tools include Clinical Practice Research Datalink’s ( CPRD ) Speedy Patient Recruitment Into Trials ( SPRINT ) and NHS DigiTrials, which use data to deliver studies from feasibility and recruitment, to monitoring participant outcomes during and after the study completes.

These actions will lay the foundations for a fully data-enabled clinical research environment that will in turn support increased recruitment, more diverse participation and the rapid development of new technologies, treatments and techniques – from precision medicines to AI -enabled diagnostics – which can help to tackle the NHS’s most pressing healthcare challenges.

As the first step towards a more cohesive data-enabled digital research environment, we commit to support the following actions.

Action area 3: increasing the use of innovative research designs

Innovative study designs have never been so widespread and so necessary throughout clinical research. Changing the way we design and deliver studies will allow us to build system resilience and increase system capacity, by freeing up NHS and research delivery staff to work on the activities that really need their involvement and skills.

Our commitments will support researchers to design their studies in more innovative ways through detailed guidance, expert advice, evaluation and showcasing the delivery of such approaches in practice. We will also increase our understanding of the barriers to implementation of innovative approaches through new methodology research. And we will use this improved understanding as a basis for the design of interventions in the next phase of the programme to enable a step change in study design, delivery and evaluation.

As the first step to deliver faster, more efficient and more innovative clinical research in the UK, we commit to support the following actions.

Action area 4: aligning our research programmes and processes with the needs of the UK health and care systems

COVID-19 has created a completely new set of needs in our health and care system. While this has generated significant demand for research evidence and new products and treatments, it has also demonstrated the critical link between clinical research and improved patient care. Aligning programmes with current and future demands for UK health services will enable us to direct clinical research capability towards the most pressing challenges facing the NHS – to bring the greatest benefits to patients across the UK and around the world.

Our commitments, initially being progressed by NHSEI , will help us to better understand these demands, both now and in the future, so that we can work with industry, medical research charities and public funders to pioneer research into the latest treatments, technologies and techniques. This will support the rapid uptake and spread of these innovations across the NHS, once they are approved.

We will also initiate a programme of work to develop, sustain and support our research delivery workforce in the NHS – by developing new professional roles, by expanding our flexible workforce and delivery models, and by increasing capacity for research in primary and community care.

As the first step to ensure world-class research is aligned to the greatest needs of the UK healthcare systems, we commit to support the following actions.

Action area 5: improving visibility and making research matter to the NHS

As highlighted in our vision, NHS sites that are active in clinical research see improved health outcomes not just for those participating in research, but for all patients. In addition, investment in clinical research leads to economic benefits for the NHS that can support frontline services including the development and retention of the workforce.

But despite these many benefits, research delivery is not as visible across the NHS as it should be. While we capture a lot of data about the research activity taking place across the UK, the metrics we apply in monitoring performance – and their consequences – can have unintended results which move us away from the aims of the vision rather than towards them.

Our commitments in the coming year will ensure we better understand these data, considering the impact current metrics, measures and incentives have on performance, and using this to drive new approaches. We will also increase awareness of research among NHS leaders and work with regulatory bodies to embed research in standards for registered professionals.

As the first step to embed research as an essential and rewarding part of effective patient care, we commit to support the following actions.

References:

• The correlation between National Health Service trusts’ clinical trial activity and both mortality rates and care quality commission ratings: a retrospective cross-sectional study
• Patients admitted to more research-active hospitals have more confidence in staff and are better informed about their condition and medication: Results from a retrospective cross-sectional study

Action area 6: making research more diverse and more relevant to the whole of the UK

We are committed to diversifying research demographics and democratising research access, particularly for communities under-served by research. We will learn from centres of excellence to understand the practices and approaches which increase confidence and willingness to participate in research and identify the mechanisms that can appropriately increase their use and access across the research ecosystem. We will also improve data collection on diversity, to monitor progress and focus further activity.

This will help us to form an accurate picture of the diversity of research participants, building on our understanding of how clinical research can increasingly be utilised to address health inequalities and improve health outcomes for everyone across the UK and around the world. This approach will empower researchers to fulfil their duty in carrying out representative research, providing detailed insights as to where barriers persist and highlighting effective techniques to bolster research participation among communities.

As the first step to ensure research is more diverse and reflective of all communities, we commit to support the following actions.

Action area 7: strengthening public, patient and service user involvement in research

The UK is world-leading in public, patient and service user involvement in clinical research. We recognise and value the unique insights that patients, carers and the public can contribute to the design and delivery of clinical research. This makes studies more effective, more relevant and often more cost effective.

Our commitment is to continue to set the global standard for good practice in public involvement in research design and management. This will ensure the public, patients and service users feel increasingly empowered to contribute to clinical research, and that researchers are supported to work effectively with them.

As the first step to expand public, patient and service-user involvement in research, we commit to support the following actions.

Governance and future actions

As set out in The Future of UK Clinical Research Delivery , the implementation of our UK-wide vision for clinical research will be delivered in 2 key phases.

Phase 1: delivery of 2021 to 2022 implementation plan

Phase 1 is delivery of this implementation plan for 2021 to 2022. This detailed plan is fully funded and has been developed by the UK government and devolved administrations in collaboration with the clinical research community, and our delivery partners through the UK Clinical Research RRG programme.

The RRG programme board brings together the delivery partners across the UK to provide system leadership, oversight and strategic co-ordination of the work to realise our shared aspirations for UK clinical research delivery. Partners in this work include:

• the UK health departments
• Health and Social Care Northern Ireland
• representatives from the MedTech Industry

Given the scope of the work and the fast pace of change in clinical research, we will keep the specifics of this plan under review via the RRG programme and adapt delivery as needed. This flexibility will allow us to meet emerging challenges and ensure that the outcomes of this plan are aligned to the most pressing issues to realise our shared aspirations.

The programme is supported by an advisory group including representatives from industry, medical research charities, academia, NHS Research and Development, representatives of the research delivery workforce across NHS settings, patient and public representatives, UK Research and Innovation ( UKRI ), the Royal College of Physicians and Royal College of Nursing’s Research Nurse Subcommittee, NIHR , and NHSEI regions.

An oversight group, chaired by the Department of Health and Social Care ( DHSC ) Minister for Innovation and composed of senior representatives from our partner organisations, industry, medical research charities, the NHS and academia, provides strategic direction and co-ordination.

Phase 2: next steps

Phase 2 is the next step in our journey. Once delivery in 2021 to 2022 is underway, we will continue to co-ordinate across delivery partners and the clinical research community to develop ambitious future strategies and plans in support of the key themes and areas of action within the vision.

In preparing for phase 2 we will consider new investment, future fiscal events, emerging scientific advances and wider changes to the clinical research landscape to set our sights towards a multi-year implementation plan, which can deliver on our vision and unleash the true potential of UK clinical research.

Most notably, we will continue to focus our efforts to embed clinical research across the NHS, by bolstering system capacity and nurturing a research-positive culture where all staff are supported to participate in research delivery. We will also work to identify the research that is most needed and align research programmes with current and future demands for health services. This will ensure we support sustainable change across the UK research community, so that the NHS is well equipped to meet the healthcare challenges of the future and that people across the UK continue to benefit from the latest improvements in healthcare delivery.

For the purposes of this document, all references to the NHS include equivalent bodies across the UK and devolved administrations, including HSCNI .  ↩

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Our Mission: Unify the voice of the global clinical research site community for greater site sustainability.

The Society for Clinical Research Sites (SCRS) is the leading advocacy organization dedicated to unifying the voice of the global clinical research site community. Representing more than 11,000+ sites in 54 countries, SCRS facilitates industry collaborations and conversations dedicated to site-focused advocacy, education, mentorship and connection. SCRS founder Christine Pierre described the founding principle of the organization: “We are all aware that as an industry we currently have an unsustainable model – for all stakeholders. Sites represent the largest number of providers to the industry; therefore, their impact on this process cannot be underestimated. Sites have long been the silent partner in the research enterprise, and SCRS ensures they are no longer passive participants by catalyzing dialogue with industry leaders and working to find solutions through collaboration.”

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On behalf of its site members, SCRS publicly comments on issues relevant to the clinical research industry. SCRS maintains a presence in conversations with other groups and organizations to ensure the site’s perspective and voice is clear as important dialogue occurs.

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Recognizing the importance and commitment needed to ensure site sustainability, SCRS and its members provide meaningful mentoring to facilitate a lasting foundation of quality research sites.

SCRS provides a unique opportunity for sites and industry stakeholders to interact with each other across the industry. The SCRS community is an environment characterized by meaningful and lasting partnerships.

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Clinical Research Facilities (CRFs) for Experimental Medicine are dedicated facilities where specialist clinical research and support staff from universities and NHS Trusts work together on patient-orientated commercial and non-commercial experimental medicine studies.

CRFs are designed to support high-intensity studies and overnight stays. Life science companies can access assistance for their studies throughout the research process from study design to data collection and management, for more information visit the  Industry Page .

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Updated MHRA Authorisation and Safety Reporting Guidance On March 25, 2024, the Medicines and Healthcare Products Regulatory Agency (MHRA) updated the Clinical Trials for Medicines: Manage Your Authorisation, Report Safety Issues . From June 1, 2024, the MHRA will only accept online payment of charges for annual safety reports via MHRA Pay prior to submission. Failure to provide evidence of payment will result in the submission being made invalid.

MHRA Announces New Streamlined Notification Scheme

On October 12, 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) announced a new streamlined notification scheme. Under the new scheme, initial applications for Phase 4 and the lowest-risk Phase 3 trials will be processed within 14 days as long as the sponsor can demonstrate the trial meets specific criteria. For more details, see the updated guidance, Clinical trials for medicines: apply for authorization in the UK .

New HRA Participant Information Standards and Principles

Effective December 1, 2023, the United Kingdom's (UK's) Health Research Authority (HRA) launched the new Participant Information Quality Standards and Participant Information Design and Review Principles . The Quality Standards and Design and Review Principles intend to make participant information clearer and more consistent and the Research Ethics Committee review process more consistent. For more information, see the HRA news alert and the Frequently Asked Questions .

See the UK’s guidance and regulation webpage for the latest information.

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Uk profile updated, uk: hra issues new final report form, uk: mhra announces combined regulatory and ethics review starting in 2022, uk profile updated in clinregs, uk: hra launches fast-track ethics review pilot, uk: brexit update and related mhra guidance, united kingdom: mhra issues guidance for clinical trials post-brexit transition period, united kingdom: mhra issues guidance for clinical trials impacted by covid-19.

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Medicines and Healthcare Products Regulatory Agency (MHRA)

As per the MHCTR and the MHCTR2006 , the Medicines and Healthcare Products Regulatory Agency (MHRA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in the United Kingdom (UK). The MHRA grants permission for clinical trials to be conducted in the UK in accordance with the MHCTR and the MHCTR2006 .

According to GBR-57 , the MHRA is an executive agency within the Department of Health and Social Care (DHSC) . MHRA’s responsibilities are to:

• Ensure that medicines, medical devices, and blood components for transfusion meet applicable standards of safety, quality, and efficacy
• Ensure that the supply chain for medicines, medical devices, and blood components is safe and secure
• Promote international standardization and harmonization to assure the effectiveness and safety of biological medicines
• Help to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices, and blood components
• Support innovation and research and development that is beneficial to public health
• Influence UK and international regulatory frameworks so that they are risk-proportionate and effective at protecting public health

Per the G-CTAuth-GBR , the agency’s Clinical Trials Unit (CTU) focuses specifically on reviewing applications to conduct clinical trials of medicinal products.

Pursuant to the MMDAct , the Secretary of State for DHSC is authorized to make clinical trials regulations and amend or supplement the law relating to human medicines, taking into consideration the safety of human medicines, the availability of human medicines, and the likelihood of the UK being seen as a favorable place to carry out research relating to human medicines, conduct clinical trials, or manufacture or supply human medicines.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing ( GBR-5 ), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48 .

Contact Information

Per GBR-58 , the following is the MHRA’s contact information:

Medicines and Healthcare Products Regulatory Agency 10 South Colonnade Canary Wharf LONDON E14 4PU UK

Main Phone: +44 020-3080-6000 Fax: +44 0203-118-9803 General Email: [email protected] Data Protection Email: [email protected] Importing Investigational Products from Approval Countries Email: [email protected]

Clinical Research Office: Email: [email protected] Phone: +44 020-3080-6456

In addition, the G-CTAuth-GBR includes other email addresses for specific purposes related to submissions.

In accordance with the MHCTR and the MHCTR2006 , the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The MPHFR and the G-CTApp specify that the scope of the MHRA’s assessment includes all clinical trials (Phases 1-4). Per G-CTApp and G-IRASCombRev , all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process (formerly known as Combined Ways of Working (CWoW), which offers a single application route and parallel/coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Regarding licensing of biosimilars (i.e., generic biotech medicines), see the G-Biosimilars for details on the UK’s recent regulatory changes to ease or remove clinical trial requirements for the MHRA’s review and approval of biosimilars.

Clinical Trial Review Process

Per GBR-72 , under combined review, research teams make a single application using a new part ( GBR-125 ) of the Integrated Research Application System (IRAS) ( GBR-78 ), which goes to both the MHRA and an EC at the same time. The regulatory and ethics reviews are done in parallel and any requests for further information are raised jointly. A single response to these requests leads to a single decision from both reviews. The G-CTApp states that t he initial combined review assessment will be completed within 30 days of application submission. Applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and the MHRA will work with the EC to expedite these applications. When applications need expert advice, the MHRA will seek advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM) . In addition, the CHM will then discuss the trial at their meeting, which will take place later in the same week as the CTBV EAG meeting. See the G-CTApp for examples of which trials require expert advice and for detailed requirements. The MHRA also supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. These trial designs are characterized by the presence of prospective major adaptations, such as the addition of new IPs or introducing new trial populations. Before submitting a clinical trial application with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

Pursuant to the combined review process, the MHRA will inform applicants of the outcome of the submission along with the EC’s review and decision. The outcomes could be one (1) of the following:

• Acceptance of the request for a clinical trial authorization
• Acceptance of the request for a clinical trial authorization subject to conditions
• Grounds for non-acceptance of the request for a clinical trial authorization

With respect to grounds for non-acceptance, applicants will have the opportunity to respond, usually within 14 days; however, this may be extended on request. A communication informing the applicant of the combined MHRA and EC decision will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of a decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application, unless otherwise advised. Communications will be sent electronically via email from [email protected] . The MHRA will only send official correspondence to the named applicant email address. According to the MHCTR , if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered authorized. (See the Timeline of Review section for additional details.)

Per GBR-9 , the EC’s ethical opinion applies for the duration of the study, which was stated in the clinical trial application and protocol. An extension of the study period is not in itself a substantial amendment, except where it is related to other amendments that would be substantial, such as an increase in target recruitment, addition of new procedures or sub-studies, or extension of follow-up. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified.

IRAS ( GBR-78 ) is a single system for applying for the permissions and approvals for health and social care/community care research in the UK. It generates the IRAS ID and uses filters to ensure that the data collected and collated is appropriate to the type of study, and consequently the permissions and approvals required. The system helps applicants meet the regulatory and governance requirements. As described in GBR-67 , approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29 .

Brexit Background

Per the G-MHRASubmiss , Brexit , the EUCouncil-Brexit , the WithdrlAgrmt , and the G-AfterTransition , the UK withdrew from the European Union (EU) on January 31, 2020. The MHRA updated and published clinical trials guidance that became effective on January 1, 2021. G-AfterTransition summarizes the guidance to sponsors and researchers. Furthermore, the G-MHRASubmiss describes how to make certain regulatory submissions to the MHRA (substantial amendments, end-of-trial notifications, and developmental safety update reports (DSURs)). Per the MHCTR-EUExit and as explained in GBR-115 , the new guidance went into force via the MHCTR-EUExit (also known as the "Exit Regulations"). The Exit Regulations also update existing UK legislation by, for example, replacing references to EU databases with newly established UK databases. The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119 . For broader information and a comprehensive Brexit “checker” of new rules in the UK, see GBR-60 .

To help ensure the continuity of supply of IPs for clinical trials the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain EU regulatory processes for a time-limited period. This recognition is known as “standstill.”

GBR-115 indicates that the UK is committed to being as aligned as possible with the EU Clinical Trials Regulation ( GBR-21 ). The MMDAct grants authority for regulations to be made that correspond or are similar to GBR-21 .

As per the MHCTR , the MHCTR2006 , and the G-CTApp , the sponsor or the designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt , applicants will receive an invoice to make a payment for the outstanding amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees.

As delineated in the G-MHRAFees , the MHRA levies the following clinical trial processing fees:

• 3,366 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier
• 248 British Pounds – Applications without an IMP dossier
• 248 British Pounds – Clinical trial variation/amendment
• No cost – Phase 4 notification
• 248 British Pounds – Assessment of annual safety reports

The G-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme.

Payment Instructions

According to the G-MHRAPaymt , the MHRA does not accept checks. Payments can be made electronically by bank transfer, credit card, or debit card. Bank transfers should be sent to:

Account Name: MHRA Account Number: 10004386 Sort code: 60-70-80 Swift code: NWBKGB2L IBAN: GB68NWBK60708010004386 Bank: National Westminster Bank

Bank address: National Westminster Bank RBS London Corporate Service Centre, 2nd Floor 280 Bishopsgate London EC2M 4RB UK

As per G-MHRAPaymt , credit or debit card payments may be made securely online using MHRA’s payments service ( GBR-26 ). Remittance advice notices can be sent to [email protected] and should include the relevant invoice number on the remittance advice. MHRA cannot accept any documentation sent by postal mail service. Further information can be obtained by emailing [email protected] . G-MHRAPaymt further provides that clinical trial application invoice disputes/queries should be emailed to [email protected] and cc: [email protected] .

The G-CTApp indicates that invoices for clinical trial authorization applications and substantial amendment applications are sent directly to the applicant shortly after a valid submission has been established. The applicant’s cover letter should clearly highlight the purchase order (PO) number where available. It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. For additional information, applicants may contact the MHRA Finance Department at 020 3080 6533 or [email protected] .

As set forth in GAfREC , the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), known as research ethics committees (RECs) in the UK. ECs are part of an accountable and independent Research Ethics Service (RES) ( GBR-62 ).

As described in GBR-51 and GBR-62 , the RES has a dual mission to protect the rights, safety, dignity, and well-being of research participants and to facilitate and promote ethical research that is of potential benefit to participants, science, and society. To achieve this, GBR-62 states that the RES works with the devolved administrations to conduct the following activities:

• Provide robust, proportionate, and responsive ethical review of research through ECs
• Provide ethical guidance to ECs
• Provide and deliver a managed structure to support ECs
• Deliver a quality assurance (QA) framework
• Deliver a training program
• Work with colleagues across the UK to maintain a UK-wide framework for ethical review
• Work with colleagues in the wider regulatory environment to streamline the processes for approving research
• Promote and support transparency in research

As stated in GAfREC , the RES encompasses England’s Department of Health and Social Care (DHSC) , Northern Ireland’s Department of Health , the Scottish Government Health and Social Care Directorates (SGHSC) , the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the head office of the RES in England, within the Health Research Authority (HRA) , to perform some UK-wide functions on behalf of the other head offices, including performing some of the functions of the UK Ethics Committee Authority (UKECA), which is the statutory body that recognizes ECs for the review of clinical trials of investigational medicinal products (CTIMPs). (See Oversight of Ethics Committees section for more details on RES and UKECA functions.) In accordance with the MHCTR and the MHCTR2006 , ECs recognized to conduct reviews of clinical trials for CTIMPs are authorized by the UKECA.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC , the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), and GBR-9 . However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. A list of recognized ECs within the RES is available through GBR-111 . Also see GBR-64 for EC definitions.

Ethics Committee Composition

As delineated in the MHCTR and GAfREC , a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-113 for additional recommendations for composition.

Per GBR-9 , in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A) , the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page , Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC , committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

In addition to complying with composition requirements, GAfREC , GBR-113 , and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting.

Per GBR-9 , applications that have been submitted via the CTIMP combined review service will be validated by the MHRA, and EC staff do not need to undertake a formal validation check. ECs should check the application against the validation checklist and request any missing information or clarifications from the applicant if required. All validated clinical trial applications for an ethical opinion should be reviewed at a full meeting of an EC. An EC should normally hold at least 10 scheduled full meetings in each year for the purposes of ethical review of applications. Additional meetings may be held where necessary to ensure that an ethical opinion on an application is given within the relevant time limit (or to discuss matters relating to the establishment or operating procedures of the EC or for training purposes). Meetings to review applications should normally be held at intervals of one (1) month, unless there are holidays. The schedule of EC meetings for the financial year commencing on April 1 st should be agreed to by December 1 st in the previous financial year. The schedule should set out the dates, times, and venues of meetings, and the closing date for applications to each meeting. All members and deputy members of the EC should receive details of the schedule. The closing dates for full applications should normally be 14 calendar days prior to each EC meeting. In the case of applications for Phase 1 clinical trials in healthy volunteers, Type 1 ECs may adopt a later closing date for applications not less than seven (7) calendar days prior to the meeting and may accept applications booked in advance of the closing date which are submitted up to seven (7) days before the date of the meeting.

According to GBR-9 , the EC Chair is responsible for ensuring that the EC reaches clearly agreed to decisions on all matters. If the Chair is unavailable, then the meeting should normally be chaired by the vice-Chair or, if the vice Chair is also unavailable, by the alternate vice-Chair. The EC meeting should reach unanimous decisions by consensus wherever possible. Where a consensus is not achievable, a formal vote should be taken by a counting of hands. The decision of the EC should be determined by a simple majority of those members present and entitled to vote. A record should be kept of the number of votes, including abstentions, in the minutes. Where the vote is tied, the Chair may give a casting vote, but should first consider any other options to arrive at a more consensual decision. Where any member wishes to record a formal dissent from the decision of the committee, this should be recorded in the minutes but should not be included in the opinion letter. An agenda should be prepared for an EC meeting. EC staff must prepare minutes of the EC meetings. See GBR-9 for additional requirements on the agenda, meeting conduct/decisions, and minutes during full EC meetings.

As per GBR-9 , documents for EC meetings should be distributed as soon as possible after the agenda is finalized and applications have been validated, and in any case no later than 10 calendar days prior to the meeting (with the exception of expedited, proportionate review, and Phase 1 applications where there has been prior agreement). Under no circumstances should full applications be tabled at the meeting. Applications should be made available to members via the HRA Assessment and Review Portal (HARP) as soon as the application is validated, and an email sent to the EC members to inform them the application is now viewable.

GBR-9 requires ECs to retain all the documentation relating to a CTIMP on which it gives an opinion:

• Where the trial proceeds, for at least three (3) years from the conclusion or early termination of the trial
• Where the trial does not proceed (e.g., it is given an unfavorable opinion, or does not start following a favorable opinion), for at least three (3) years from the date of the opinion

In accordance with GBR-9 , documentation should be retained on all invalid applications for at least one (1) year from the date of invalidation; and for three (3) years where the application is withdrawn by the EC, the chief investigator, or the sponsor after the EC review but before a final opinion is given. Signed final copies of the minutes of full EC meetings and sub-committee business should be retained electronically for at least 20 years. Where paper records are destroyed in accordance with this policy, they should be shredded and disposed of as confidential waste. Electronic records of studies will be retained indefinitely.

For detailed EC procedures and information on other administrative processes, see GAfREC , GBR-113 , and GBR-9 . Also see GBR-8 for a summary of changes to GBR-9 .

According to GAfREC , the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), and GBR-9 , the primary scope of information assessed by ethics committees (ECs) within the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) ( GBR-62 ) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK). GAfREC specifies that ethical review is required for research proposals that involve investigational products (IPs), material consisting of human cells, and other situations that are described in GAfREC .

As per GAfREC , the MHCTR , the MHCTR2006 , the MHCTR2006-No2 , and GBR-113 , ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates ; Prisoners; and Mentally Impaired sections for additional information about these populations).

As indicated in GAfREC , the MHCTR , the MHCTR2006 , GBR-113 , and GBR-9 , ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC , the MHCTR , the MHCTR2006 , and GBR-9 for detailed ethics review guidelines.

GBR-112 indicates that certain ECs are flagged for special expertise including gene therapy or stem tell clinical trials; Phase 1 studies in healthy volunteers; Phase 1 studies in participants; research involving adults lacking capacity; research involving children; research involving prisoners or prisons; or fast-track ECs.

Role in Clinical Trial Approval Process

As described in GBR-9 , GBR-66 , and GBR-95 , the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. Per GAfREC and GBR-9 , ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA) to conduct reviews of clinical trials for IPs (known as clinical trials for investigational medicinal products (CTIMPs) in the UK). Per GAfREC , RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than IP clinical trials. Also see GBR-64 for definitions of EC terminology and GBR-111 and GBR-112 to search for ECs within the RES.

As indicated in the MHCTR , the MHCTR2006 , and GAfREC , IP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or the designated legal representative initiating the trial. The G-CTApp states that all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, wherein a single application route and coordinated review by MHRA and the EC leads to a single UK decision. New clinical trial applications for combined review are prepared and electronically submitted to the new combined review section of Integrated Research Application System (IRAS) ( GBR-125 ). Per GBR-78 , IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies. According to GBR-9 , submissions of the electronic application must be made to IRAS on the same day that a booking is made to schedule an EC review through the NHS REC’s Online Booking Service ( GBR-95 ).

According to the MHCTR , GAfREC , and GBR-9 , for all studies, only one (1) EC review (referred to as the “main EC”) is needed for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the CI should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

Per GBR-68 , unless an application is being processed under the proportionate review service, the applicant should attend the EC meeting if possible. The EC will notify the sponsor of its decision, usually within 10 working days of the EC meeting. GBR-9 indicates that the EC should reach one (1) of the following decisions on any application reviewed at a full meeting or a proportionate review sub-committee meeting:

• A final opinion, which may be either favorable with standard conditions, favorable with additional conditions, or unfavorable
• Provisional opinion with request for further information, which means the EC may decide that a final opinion cannot be issued until further information or clarification has been received from the applicant

The MHCTR , GBR-9 , and GBR-68 state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR . (See the Submission Process and Timeline of Review sections for detailed submission process requirements.)

Per GBR-116 , the Health Research Authority (HRA) , on behalf of the UK, offers a fast-track research ethics review. Fast-track ethics review is open to global clinical trials and Phase 1 trials, whether the sponsor is commercial or non-commercial. This includes:

• Any clinical trial of an investigational medicinal product (CTIMP) led from UK with at least one (1) other country participating
• Any CTIMP led from outside the UK which could be placed in any country and the UK is competing for participation (including any only taking place in the UK)
• Any Phase 1 or Phase 1/2 CTIMP in healthy volunteers or participants

Fast-track ethics review is not available for any CTIMP involving a gene therapy medicinal product, any CTIMP funded by the US Department of Health and Human Services , and any other type of clinical trial or research study.

Per GBR-9 , the EC’s favorable ethical opinion applies for the stated duration of the study, except where action is taken to suspend or terminate the opinion. The MHCTR , GAfREC , and IRAS ( GBR-78 ) require the applicant to identify an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment.

GBR-9 describes EC processes related to reviewing and approving clinical trial amendments and any related notifications. The sponsor of a CTIMP may make an amendment to a clinical trial authorization, other than a substantial amendment, at any time after the trial has started. These do not need to be notified. If the amendment is substantial, the sponsor is required to submit a valid amendment to the MHRA and/or the REC that gave the favorable opinion of the trial. Where the sponsor requests an ethical opinion on a CTIMP, the EC should provide this in all cases within 35 calendar days of receiving a valid amendment. If the opinion is unfavorable, the sponsor may then modify the proposed amendment. A written notice of the modification should be sent to the main EC at least 14 calendar days before it is due to be implemented. The EC may then give an unfavorable opinion on the modified amendment within 14 calendar days, otherwise it may be implemented. See GBR-9 and GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA. GBR-9 states that while the EC is not responsible for proactive monitoring, it has a duty to keep the favorable ethical opinion under review in the light of progress reports and significant developments and may review the opinion at any time. If information raises concerns about the suitability of the site or investigator, the favorable opinion may be reviewed.

As set forth in GAfREC , ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

As stated in GAfREC and GBR-9 , the United Kingdom (UK)-wide Research Ethics Service (RES) ( GBR-62 ) provides proportionate and responsive ethical review of research through its “recognized” ethics committees (ECs), known as research ethics committees (RECs) in the UK. Per the MHCTR , the MHCTR2006 , and GAfREC , the UK Ethics Committee Authority (UKECA) is the statutory body that recognizes ECs for the review of clinical trials of investigational products (CTIMPs). The UK Health Departments have authorized England’s Health Research Authority (HRA) to perform some of the RES functions (more details below).

As indicated in the MHCTR and GBR-9 , the UKECA recognizes two (2) types of ECs for new CTIMPs:

• Type 1: Reviews Phase 1 clinical trials of investigational products (IPs) taking place at any site in the UK, where the sponsor has no knowledge of any evidence that the product has effects likely to be beneficial to the participants of the trial, and the participants are healthy and not suffering from the disease or condition to which the trial relates.
• Type 3: Reviews clinical trials of IPs taking place at any site in the UK, including first-in-person studies involving people with the target disease or condition to which the trial relates.

As stated in GAfREC , the HRA performs the following EC oversight activities on behalf of the UKECA:

• Develops and manages a national training program for ECs
• Develops, implements, and maintains standard operating procedures for ECs and provides advice and support to ECs on procedural issues
• Develops a quality assurance program, including accreditation of ECs, based on regular monitoring and audit of their operation and performance
• Provides guidance and advice to assist ECs in their work and encourage consistency of approach to common issues in research ethics
• Acts for UKECA to provide a national mechanism for operational advice and assistance to ECs recognized to review and approve clinical trials
• Acts for UKECA to handle appeals against the unfavorable opinions of ECs in respect of CTIMPs
• Acts for UKECA to transfer to a successor EC the functions of an EC that has ceased to operate or that has been varied, abolished, or had its recognition revoked
• Acts for UKECA to reallocate to ECs applications made to the Gene Therapy Advisory Committee which do not require its review

The following oversight functions are the responsibility of UKECA for the purposes of clinical trials:

• Establishes or recognizes ECs
• Establishes or recognizes ECs to act in relation to such descriptions or classes of research as it considers appropriate
• Abolishes or revokes the recognition of ECs that it has established or recognized
• Monitors the extent to which ECs adequately perform their functions, including through annual reports from ECs it has recognized
• Approves standing orders and standard operating procedures for EC business and operations, as well as variations and revocations to these orders and procedures

Registration, Auditing, and Accreditation

Per GAfREC , HRA, acting for UKECA, develops a quality assurance program to encourage a consistently high level of service to applicants, including accreditation of ECs, based on regular monitoring and audit of their operation and performance.

GBR-123 indicates that HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in GAfREC and GBR-9 . ECs are issued with an audit decision: full accreditation, accreditation with conditions (low-risk non-compliance identified requiring an action plan), or provisional accreditation (high- and low-risk issues requiring an action plan). Published bi-annually, HRA’s latest accreditation report is at GBR-124 . In addition, q uality control checks are undertaken, and results are shared with management teams. For example, operational managers observe EC meetings and provide a check against agreed-upon standards relating to meeting conduct and minute taking. Findings from the meeting observations are shared with the EC chair and staff and collated to identify common themes to inform improvements. For more information about quality assurance, contact [email protected] .

In accordance with the MHCTR , the MHCTR2006 , the G-CTApp , and GBR-9 , the United Kingdom (UK) requires the sponsor or the designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. Per G-CTApp and G-IRASCombRev , the UK’s combined review process offers a single application route and coordinated/parallel review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Note: G-CTApprovedCountries and the MHCTR-EUExit list the countries where a clinical trial sponsor or their legal representative may be established; these countries are initially European Union (EU) and European Economic Area (EEA) countries.

Combined Review Submission

Per G-CTApp and G-IRASCombRev , all new clinical trials applications of investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process using the Integrated Research Application System (IRAS) ( GBR-125 ). For support and getting started, users should review GBR-72 and contact the combined review team at [email protected] . Step-by-step instructions are provided in G-IRASCombRev . As delineated in GBR-9 , applications submitted via the combined review service are submitted jointly by the chief investigator and the sponsor. Per GBR-116 , applicants seeking fast-track review of clinical trial applications must also apply via combined review on GBR-125 . See Scope of Assessment section for fast-track eligibility criteria.

Per GBR-122 , for studies that were submitted before combined review, these applicants should continue to submit amendments and reports for these studies at IRAS via GBR-78 ’s log-in. HRA will update sponsors and applicants with full instructions and plenty of notice for any planned changes in the future, such as the migration of existing, ongoing studies. See GBR-122 , for additional details on the migration of existing materials in IRAS. GBR-72 includes learning resources and a video on the combined review process.

G-IRASCombRev contains a step-by-step guide to combined review submission. The following is an overview of the steps:

• Finalize protocol and supporting documents
• New users create IRAS account and create a new project and allocate roles
• Complete project details, study information, and clinical trial dataset in IRAS and upload supporting documentation
• Send application to the sponsor to review and authorize
• Book an EC online and submit application

Note that when selecting an EC meeting that is not the first available meeting, the 60-day regulatory clock for both the EC and the MHRA will start on the cutoff date for the meeting that is chosen, which is 14 days before the meeting date. Once booked, the EC booking page will update to show the confirmed booking details. The applicant will then be able to scroll down the page to select the option to “submit to the regulators.” See G-IRASCombRev for detailed step-by-step instructions.

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss . These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth-GBR also states that clinical trials not approved or yet transitioned over to the combined review process should continue to use the online MHRA Submissions portal ( GBR-13 ). The steps for gaining access to the UK portal MHRA Submissions ( GBR-13 ) are contained in the G-MHRASubmiss and GBR-11 . For overviews of submittals to MHRA, see GBR-18 and GBR-17 .

Per GBR-18 , a ll CTIMPs that have sites in the EU must be registered on the EudraCT database ( GBR-87 ) and issued with a unique EudraCT number.

As described in GBR-78 , other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

Per G-CTApp , MHRA supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. When submitting a clinical trial application for a trial with innovative designs that involve prospective major adaptations, the sponsor must justify the choice of a complex trial design, ensure that each adaptation as well as the entire trial are safe and scientifically sound, and describe how the integrity of trial results will be maintained throughout the conduct of the trial. See G-CTApp for example scenarios of when it is appropriate to propose major adaptations via submission of a substantial amendment request. Before submitting an application for authorization of a trial with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

As delineated in the MHCTR , the clinical trial application and accompanying material must be provided in English.

Regulatory Authority Requirements

As specified in the G-CTApp , a clinical trial submission package to the Medicines and Healthcare Products Regulatory Agency (MHRA) should contain the following documents:

• Cover letter (when applicable, the subject line should state that the submission is for a Phase 1 trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme); this letter should clearly highlight the Purchase Order (PO) number to help the MHRA invoice and allocate payments promptly and efficiently
• Clinical trial application form in PDF and XML versions
• Protocol document
• Investigator’s brochure (IB)
• Investigational medical product dossier (IMPD) or a simplified IMPD
• Summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
• Manufacturer’s authorization, including the importer’s authorization and Qualified Person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the European Union (EU) (See G-ImportIMPs and the Manufacturing & Import section for more information)
• Copy of the United Kingdom (UK) or the European Medicines Agency ’s decision on the pediatric investigation plan and the opinion of the pediatric committee, if applicable
• Content of the labelling of the investigational product (IP) (known as investigational medicinal product (IMP) in the UK) (or justification for its absence)

Ethics Committee Requirements

As per the MHCTR , the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), ECs require the chief investigator (CI) to submit the following documentation for ethics approval:

• Application for an EC opinion
• A summary of the trial, including justification, relevance, and methodology to be used
• Research hypothesis
• Statistical analysis and justification for the numbers of participants to be recruited
• Peer review process details
• Sponsor name and contact information
• Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (See the Insurance & Compensation section for additional information)
• Terms of agreement between sponsor and participating institution(s)
• Material to be used (including advertisements) to recruit potential research participants
• Informed consent form and copies of materials to be provided to participants (See the Required Elements section for additional information)
• Participant treatment plans
• Benefit/risk assessment for participants
• Investigator(s) Curriculum Vitaes (CVs)
• Trial design and suitability of facilities

Further, to help with planning before seeking EC approval, GBR-18 provides a checklist for CIs.

Clinical Protocol

Per GBR-9 , the protocol describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. According to GBR-113 , the clinical protocol should contain the following elements:

• Protocol summary
• Sponsor or designated representative name and contact information
• Investigator(s) CV(s) and contact information
• IP description (See the Investigational Products topic for detailed coverage of this subject)
• Form, dosage, route, method, and frequency of administration; treatment period
• Trial objectives and purpose
• Trial design, random selection method, and blinding level
• Participant selection/withdrawal
• Participant treatment
• Summary of potential risks and known benefits to research participants
• Safety and efficacy assessments
• Adverse event reporting requirements (See the Safety Reporting section for additional information)
• Statistics and methods to track trial data
• Sponsor specifications for direct access to source data/documents
• Quality control/quality assurance procedures and practices
• Ethical considerations
• Data management and recordkeeping
• Financing and insurance details
• Publication policy

For complete protocol requirements, refer to GBR-113 .

Per G-CTApp and G-IRASCombRev , all new clinical trials applications for investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process. Combined review offers a single application route and coordinated/parallel review from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) leading to a single United Kingdom (UK) decision for clinical trials.

Combined Review

Per the G-CTApp and GBR-72 , the initial combined review assessment will be completed within 30 days of being submitted. The G-CTApp indicates that applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and MHRA will work with the EC to expedite these applications. The MHRA and the EC will inform applicants of the outcome of a submission. If there are grounds for non-acceptance of the application, the applicant will have the opportunity to respond--usually within 14 days, though this may be extended on request. Communication informing the applicant of the MHRA and EC decisions following receipt of the responses will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application unless otherwise advised.

The G-CTApp states that the MHRA uses automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add [email protected] to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR , if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

In addition, as stated in the G-CTApp , certain first-in-human (Phase 1) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines before approval for the trial can be given. See the G-CTApp for detailed requirements.

In accordance with the MHCTR , the MHCTR2006 , and GAfREC , a clinical trial can only commence after the sponsor or the designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). In addition, GBR-9 clarifies that a favorable EC opinion does not imply that research activity at sites can begin. Confirmation of management permission or approval from relevant care organization(s) to proceed with the research also needs to be in place. In addition, if the EC issued a favorable opinion with additional conditions, the clinical trial cannot start until these conditions are met. Finally, per the MHCTR and GBR-18 , specific documentation, including MHRA licensing, must be in place before an investigational product (IP) can be released for a clinical trial.

As stated in the MHCTR , clinical trials should be conducted in compliance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), and laboratory practices for IPs must comply with the UK-GLPs .

Per GBR-78 , all project-based research must also have governance and legal compliance approvals from the appropriate lead United Kingdom (UK) Health Department. The Integrated Research Application System (IRAS) ( GBR-78 ) facilitates this process. As described in GBR-67 , approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29 .

Clinical Trial Agreement

According to GBR-107 and GBR-70 , contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates for industry-sponsored clinical trials with the NHS/ Department of Health and Social Care (DHSC) participants in hospitals throughout the UK Health Services, which encompasses England, Northern Ireland, Scotland, and Wales. Applicants are advised to use the templates without modification. Any proposed modifications will not be accepted unless first agreed to by the UK Contracting Leads. Proposing modifications to the templates is likely to result in significant delay. Feedback on the content of the templates and their use by sponsors should be provided to [email protected] .

GBR-107 also provides the model non-commercial agreement (mNCA) template to meet the requirements of non-commercial sponsors and the NHS/DHSC bodies undertaking the research. This agreement has been developed as a single, UK-wide agreement template, meaning that it can be used irrespective of where the sponsor and research site are established. It is designed to be used without modification or negotiation. The mNCA has been developed for a range of interventional research scenarios, including clinical trials, medical device studies, research using participant data, and research using human tissue. The terms and conditions are suitable for all such scenarios and only the completion of highlighted sections, including the schedules of the agreement, will differ depending on the study involved.

Additional details and templates are available in GBR-107 and GBR-70 .

Clinical Trial Registration

As per the GBR-102 and the G-CTApp , the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. To help researchers meet the UK’s transparency requirements, GBR-102 indicates that the HRA will automatically register approved clinical trials with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry ( GBR-47 ) to ensure that information is publicly available. ISRCTN is the UK's preferred clinical trials registry. HRA’s commitment to register clinical trials on behalf of sponsors and researchers is in line with the “Make It Public” research transparency strategy (see GBR-55 ). Per GBR-102 , HRA also recognizes any registry covered by the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE) , such as clinical trials.gov ( GBR-49 ). For any submissions prior to December 31, 2021, the applicant should have registered their clinical trial on an established international register. If deferral of registration is needed, then contact the HRA at [email protected] . The registry number(s), if available, should continue to be used in section A.5. of the application form in IRAS ( GBR-78 ) when preparing the application. If this number is not available at the time of application, email the MHRA at [email protected] with subject line “Clinical Trial Registration” within six (6) weeks of recruiting the first research participant. The applicant should also let the EC know the registration number as soon as possible.

Safety Reporting Definitions

According to GBR-1 and GBR-64 , the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

• Adverse Event or Adverse Experience (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
• Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
• Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected SADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
• Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
• Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction, which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question.

Per the G-CTAuth-GBR , the Medicines and Healthcare Products Regulatory Agency (MHRA) advises that the guidance on reference safety information (RSI) contained in GBR-30 (developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA) ) remains applicable. For clinical trials that are being conducted in the UK, an RSI cannot be used for expectedness until the RSI has been approved by the MHRA. Additional SUSARs that occur before the new RSI is approved should be reported in the usual expedited manner. If sponsors wish to harmonize the implementation date of an RSI in a trial that includes European Union (EU) and UK sites, then they can use the date when approval is granted in all member states and the UK. In the interest of efficiency and harmonization for multinational trials, the MHRA recommends that amendments including changes to the RSI are submitted to the UK and EU at the same time. The RSI in place at the time the SUSAR occurred should be used to assess expectedness for follow-up reports.

Safety Reporting Requirements

Per GBR-99 , a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main ethics committee (EC), and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. GBR-9 states that for trials which have been via the combined review service, one USM notification is made via of the Integrated Research Application System (IRAS) ( GBR-125 ) and received by the MHRA. No additional notification is required directly to the REC. In addition, the G-CTAuth-GBR states that the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform the MHRA no later than three (3) days from the date the measures are taken by email to [email protected] . Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. Submission of the substantial amendment must not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection. For more details on how submissions should be made using MHRA Submissions, see G-CTAuth-GBR .

Investigator Responsibilities

As specified in the MHCTR , GBR-1 , and GBR-30 , the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR , in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1 , the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

Sponsor Responsibilities

According to the MHCTR , the G-CTAuth-GBR , and the MHCTR-EUExit , the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days to the MHRA, to the institution in which the trial is being conducted, and to the EC. Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1 , the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness. Per the G-CTAuth-GBR , sponsors must report all UK-relevant SUSARs to the MHRA. The agency’s definition of ‘UK-relevant’ includes:

• SUSARs originating in the UK for a trial
• SUSARs originating outside the UK for a trial
• If the sponsor is serving as a sponsor of another ongoing trial outside the UK involving the same medicinal product
• SUSARs involving the same medicinal product if the sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the UK sponsor

Other Safety Reports

Per the G-CTAuth-GBR , sponsors must submit Development Safety Update Reports (DSURs) to the MHRA. The DSUR should consider all new available safety information received during the reporting period. The DSUR should include:

• A cover letter listing all relevant clinical trial numbers of trials covered by the DSUR and an email address for correspondence (Note: per GBR-18 , every clinical trial with a European site must include a unique European Clinical Trials Database (EudraCT) number ( GBR-87 ))
• An analysis of the participant’s safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
• A listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s)
• An aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)

At the end of the DSUR reporting period, the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB as a substantial amendment. This amendment must be supported by the DSUR and approved before the RSI is changed.

A shortened DSUR is available for approved trials under MHRA’s notification scheme that are not part of a multi-study development program. Phase 4 national (UK only) trials of licensed products, which commanded a low fee from the MHRA, and where all participants have completed treatment and are only in the follow-up stage will also be suitable for submission of a short format DSUR. As an alternative to producing a full DSUR for these trials, the Health Research Authority Annual Progress Report ( GBR-27 ) may be used.

The MHRA and Health Canada jointly released DSUR-UK_Canada to strengthen participant safety in clinical trials by improving the quality of DSURs. To increase the transparency of the data included in DSURs, the MHRA and Health Canada are requiring that the region-specific section of the DSUR explain how safety data were reviewed during the reporting period. Specifically, the region-specific section of the DSUR should include a summary description of the processes used by the sponsor to review the worldwide safety data of the investigational product (IP) (e.g., regular analyses of accumulating data, in-house safety review meetings, proposal of specific pharmacovigilance activities, or substantial modifications of the protocol). In addition, the region-specific section must describe how each safety signal (i.e., an event with an unknown causal relationship to the IP) identified during the reporting period was evaluated, as well as how a decision was made regarding the signal itself.

See the G-CTAuth-GBR , the MHCTR , GBR-1 , GBR-30 , and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

Per the G-CTAuth-GBR , SUSARs during clinical trials should be reported to the MHRA in one (1) of the following ways:

• Individual Case Safety Reports (ICSR) Submissions ( GBR-126 ) (which replaces the EudraVigilance website (EVWEB)) - The ICSR Submissions route is used to submit single reports. (Note that per GBR-127 , MHRA also decommissioned the eSUSAR reporting platform.)
• MHRA Gateway (which replaces the EudraVigilance Gateway) - To gain access to the MHRA Gateway, which is used to submit bulk reports, users must first register via MHRA Submissions ( GBR-13 ). The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11 .

If applicable, the user will need to dual report UK-relevant SUSARs to the Clinical Trial Module in the European Medicines Agency ’s EudraVigilance Clinical Trial Module , as well as to other national competent authorities, using the European submission routes.

See the G-CTAuth-GBR and GBR-99 for more details on submittal and delivery requirements.

Interim and Annual Progress Reports

As indicated in the G-CTAuth-GBR , GBR-65 , and GBR-9 the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ).

In accordance with GBR-65 and GBR-9 , the chief investigator (CI) is responsible for submitting progress reports annually, or more frequently if requested by the ethics committee (EC), on the status of a clinical trial. Per GBR-65 , a progress report should be submitted to the EC 12 months after the date on which the favorable opinion was given. Progress reports are only required for studies that are more than two (2) years in duration and for Research Tissue Bank and Research Databases. There is no requirement to submit a progress report for proportionate review studies and where the study is two (2) years or less in duration. The form ( GBR-27 ) should be completed in typescript and signed by the CI. An electronic copy should be emailed to the EC within 30 days of the end of the reporting period.

Health Research Authority (HRA) -approved research projects that have also been reviewed by an EC should submit regular progress reports to the HRA using the guidance outlined for ECs above. See GBR-18 for additional information on clinical trial progress reporting.

Final Report

As per the MHCTR and the G-CTAuth-GBR , the sponsor must notify the Medicines and Healthcare Products Regulatory Agency (MHRA) and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. As indicated in GBR-128 , a ll project-based research (not research tissue banks or research databases) that has been reviewed by an EC needs to submit a final report within 12 months of the end of the study. The final report should be completed and submitted in the combined review part of Integrated Research Application System (IRAS) ( GBR-125 ) . When completing the final report form, IRAS guides the user with instructions next to each question.

The G-CTAuth-GBR further specifies that a declaration of the end of a clinical trial should be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form ( GBR-133 ) and a cover letter. Note that only the global end-of-trial notification is required to be submitted. However, a facility may inform the MHRA of the local (UK) end of trial via the end-of-trial notification form, but these local notifications will not be officially acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, MHRA would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received. An exemption to this requirement must be requested via a substantial amendment for approval. The amendment must clearly state to what documents the proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK. Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end-of-trial declaration form. It is not possible to submit amendments to the trial or the Development Safety Update Report (DSUR) once the global end-of-trial declaration form has been received by the MHRA. If the end-of-trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

Per the G-CTAuth-GBR , the timeframe for publishing the summary of results is within one (1) year of the end of trial. Sponsors should publish summary results within this timeframe in the public register(s) where they registered the clinical trial. While it is not required to submit this clinical trial summary report to the MHRA, sponsors must send a short confirmation email to [email protected] once the results-related information has been uploaded to the public register and provide the relevant link. The G-CTAuth-GBR specifies that the subject line of the email notification must state ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ once the result-related information has been uploaded to the public register. If the clinical trial is not on a public register or the results will not be published in the register (for example an adult phase 1 study), summary results should be submitted to MHRA via MHRA Submissions ( GBR-13 ). An acknowledgement letter will not be sent for this submission. Sponsors of trials conducted in the UK that are already registered in the European Union (EU) Register may submit results to EudraCT ( GBR-87 ). The MHRA will not be able to update the status of the study in the EU system.

As per GBR-9 the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. GBR-20 clarifies that the form in GBR-20 should be used for this submittal, which includes submitting a lay summary of results. This is a UK-wide final report for all project-based research studies that have been reviewed by an EC within the UK Health Departments' Research Ethics Service ( GBR-62 ). The information contained in this final report helps the Research Ethics Service to monitor whether the research was conducted in accordance with the EC’s favorable opinion and applicable transparency requirements. Per the GBR-120 , sponsors should include a plain language summary of their findings in the final report, which will be published on HRA’s website alongside the study research summaries. See GBR-120 for guidance on writing a good plain language summary for a general audience.

Per the G-PIPs , UK marketing authorization holders who sponsor a study that involves the use of the authorized medicinal product in the pediatric population, must submit to the MHRA results of the study within six (6) months after the trial ended. Additional requirements and submittal details are in the G-PIPs and the G-PIPsProcess .

As per the MHCTR , the MHCTR2006 , the G-CTApp , GBR-103 , GBR-9 , GBR-2 , and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards and arrange for the trial to be properly conducted and reported. In addition, per GBR-101 , the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-113 , the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Per the G-CTApp , G-SubtlAmndmt , and the GBR-103 , a the clinical trial sponsor or legal representative needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per G-CTApprovedCountries . A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committ ee. The GBR-103 specifies that the legal representative:

• May be an individual person or a representative of a corporate entity
• Does not have to be a legally qualified person
• Should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted (e.g., for service of legal documents)
• Should be established at an address in the UK or a country on the approved country list
• Does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities; but may, in some cases, enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA) , and to specify who is responsible for carrying out the following functions:

• Communications relating to substantial amendments, modified amendments, and the conclusion of the trial
• Communications relating to urgent safety measures
• Pharmacovigilance reporting

Per the G-SubtlAmndmt , the UK requires the sponsor or legal representative of a clinical trial to be in the UK or a country on an approved country list that will initially include the EU and EEA countries. A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee.

As set forth in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 indicates that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. GBR-9 states that the chief investigator (CI) should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

As delineated in the MHCTR , the MHCTR2006 , and GBR-113 , prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-113 , if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. Per GBR-18 , for clinical trials of investigational products (CTIMPs) conducted at National Health Service (NHS) sites, the addition of a new site and/or addition or change of a principal investigator (PI) is no longer considered a substantial amendment. No changes have been made to the classification of amendments relating to new sites/change of PI at non-NHS sites. If a site is added in a nation not previously involved in a study, this should be indicated in the combined review section ( GBR-125 ) of the Integrated Research Application System (IRAS) ( GBR-78 ) for CTIMPs, and made clear in a cover letter when submitting the amendment to the lead nation.

GBR-113 recommends establishing a Data Monitoring Committee (DMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Per GBR-63 , researchers working with NHS/ Health and Social Care in Northern Ireland (HSC) organizations across England, Northern Ireland, Scotland, and Wales should use the UK Local Information Pack, which provides one (1) consistent package to support study setup and delivery across the UK. For help with preparing and submitting these packages and site-specific information, see GBR-106 .

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per the G-CTApprovedCountries , the UK published a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; currently listed countries are those in the EU and EEA. The G-SubtlAmndmt delineates that a change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC), pursuant to the guidelines in the G-CTAuth-GBR . Where the sponsor is from the rest of the world, and the legal representative is established in the UK, and there are sites in the EU/EEA, the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities. No amendment submission to the MHRA is required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA as the UK will continue to accept this approval. Further, no amendment will need to be submitted in the UK if the sponsor retains the UK legal representative for the UK study. Similarly, no amendment will need to be submitted in the UK if a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites.

Additional foreign sponsor requirements are listed in Section 5.2 of GBR-113 .

Data Safety and Monitoring Board

Per GBR-18 , the chief investigator should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). GBR-113 recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

As delineated in GBR-113 , in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

As set forth in the MHCTR and the MHCTR2006 , it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial-related injuries. The MHCTR does not ascribe responsibility to the sponsor or the designated representative to obtain insurance and indemnity. However, GBR-2 , GBR-103 , GBR-101 , and GBR-18 , state that the sponsor or the designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2 , the sponsor or the designated representative must ensure that the research covered by the National Health Service (NHS) 's indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33 , specifically addresses the sponsor’s or the designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase 1 clinical trials.

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ) also guides sponsors on providing insurance.

Compensation

Injury or Death

As specified in the MHCTR , the sponsor or the designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase 1 trial-related injuries or death. According to GBR-33 , the sponsor must have agreed with the research participant to provide compensation for injury whenever a causal relationship with participation is demonstrated. This undertaking can be provided directly by the sponsor through the consent process, or through authorizing the contract research organization (CRO) or investigator on behalf of the sponsor. In addition, the sponsor should follow these practices:

• If the health or wellbeing of the participant deteriorates significantly as a result of taking part in the study, the sponsor will compensate the volunteer, irrespective of the ability of the participant to prove fault on the part of the sponsor or anyone else connected with the study.
• The amount of compensation should be calculated by reference to the amount of damages that would commonly have been awarded for similar injuries by an English court had liability been proven. The amount of compensation may be reduced if the volunteer is partly responsible for the injury or if the volunteer is separately compensated under any other insurance policy.
• The sponsor and participant agree to refer any dispute about whether compensation is payable or the amount of such compensation to an arbitrator with power to consult a barrister of 10 years’ standing on any issue of law, including the amount of damages to be paid.
• Participants should be given a copy of the relevant Association of the British Pharmaceutical Industry (ABPI) guidelines and should be invited to seek clarification of any aspect of the undertaking that is not clear to them.
• Participants may make a claim through the investigator, and the sponsor should aim to respond sympathetically and promptly.

GBR-113 also provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

Quality Assurance/Quality Control

As stated in the MHCTR , the MHCTR2006 , and GBR-92 , the sponsor is responsible for maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ). The sponsor is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

• Conduct the trial in compliance with GBR-113 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to affect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches , the sponsor, or delegated party, should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: [email protected] .

Per the G-RiskAssmt , MHRA recommends that a risk assessment is undertaken for all clinical trials. Phase 1 trials are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials. The risk assessment should be done as early as possible to help the sponsor identify whether the sponsor wishes to proceed with sponsorship and also the potential category of IP for eventual marketing authorization. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g., identification of trial monitoring requirements so that these can be budgeted for in any funding application). There is no requirement to submit risk assessments to the MHRA or the ethics committee (EC). However, any safety monitoring produced as a result of the risk assessment must be described in the protocol. Finally, information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the EC application. See the G-RiskAssmt for details on how to conduct the risk assessment.

Monitoring Requirements

Per GBR-18 , the sponsor must develop an audit plan to assess and assure the reliability and integrity of the clinical trial systems against all relevant written standards. The following activities and checks could include the following:

• Interview staff to assess whether they are appropriately trained, understand their role(s), and are working to all relevant standards, the protocol and procedures SOPs.
• Tour the facility to assess if there are adequate resources and if the equipment is fit for its intended use.
• Review documents to evaluate whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.

Auditors must be independent of the trial team and appropriately trained for their role. Their findings and observations must be documented in a formal audit report. Any deficiencies identified during an audit must be followed up with appropriate corrective and preventive actions wherever possible.

Per GBR-18 , the MHRA may conduct inspections to ensure the clinical trial is being conducted in compliance with good clinical practice (GCP) as prescribed in GBR-92 and GBR-113 . The MHRA takes a risk-based approach to inspections depending on the type of trials and risk rating. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventive actions) must be produced. Per G-RiskAssmt , GCP Inspectors will review risk assessments. The risk assessment should provide the rationale behind trial management/monitoring and GCP activities applied, or not, to the trial.

Finally, the sponsor’s audits and inspections should be conducted in compliance with GBR-113 , which calls for a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials.

Premature Study Termination/Suspension

The G-CTAuth-GBR states that the MHRA has the authority to suspend or terminate a trial. In addition, the sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial. If a sponsor suspends a trial temporarily, the MHRA must be notified. Sponsors of clinical trials of investigational products (CTIMPs) must use the combined review part of the Integrated Research Application System (IRAS) ( GBR-125 ) to submit this notification as a substantial amendment. Per GBR-122 , for studies that were submitted before combined review, these applicants should continue to submit this notification at IRAS via GBR-78 . The G-CTAuth-GBR indicates the notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension. To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Per the G-CTAuth-GBR and GBR-18 , to terminate a CTIMP, the sponsor must notify (as a substantial amendment) the MHRA and the EC via the combined review part of IRAS ( GBR-125 ). For studies that were submitted before combined review, the submission should be made at GBR-78 , using the end-of-trial form (GBR-133). GBR-128 specifies that for CTIMPs, the declaration of end of trial must be sent to the MHRA within 15 days of the global premature end of trial. Before declaring an end of the study, sponsors should review the plans that were approved by the EC for use of tissue and data collected in the course of the study, providing information to participants, and dissemination of results. If changes need to be made to these agreed arrangements, the sponsor should consider whether an amendment is required before submitting the end of study notification.

According to GBR-113 , if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should also inform the EC promptly and provide the reason(s) for the termination or suspension.

Electronic Data Processing System

To safeguard personal data within electronic health record (EHR) systems, G-EHRAccess provides guidance on updating these systems to ensure access by sponsors and their representatives (e.g., monitors and investigators) is limited to only the records of clinical trial participants and that this access is auditable. See G-EHRAccess for details on system security, remote access, document sharing, consent, and other considerations.

According to GBR-113 , when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Records Management

As set forth in GBR-113 , sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006 , the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the Medicines and Healthcare Products Regulatory Agency (MHRA) upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

In addition, GBR-113 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

For purposes of data protection requirements, the UK-GDPR , the UK-DPAct , and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database. GBR-7 provides guidance on key data protection requirements to consider in the post-Brexit environment. Among other things, it describes how data can continue to flow to and from the United Kingdom (UK), as well as controller responsibilities.

Data Protection

Per the UK-GDPR , the UK-DPAct , the G-GDPR , and GBR-89 , the sponsor (known as the “controller” in data protection legislation) must comply with the following principles of the data protection legislation:

• Lawfulness, fairness, and transparency
• Purpose limitation
• Data minimization
• Storage limitation
• Integrity and confidentiality (security)
• Accountability

The sponsor must show that each data processing activity has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the data controller’s organization type:

• For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
• For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR , with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data. See the table in G-GDPR , which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100 .

Per the UK-GDPR and the UK-DPAct , the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments (DPIAs), and is a point of contact for participants and the supervisory authority. See G-GDPR for guidance related to DPIAs.

For more information on data protection requirements following the UK’s transition out of the European Union (EU), see GBR-7 .

Consent for Processing Personal Data

Per the UK-GDPR , UK-DPAct , and G-GDPR , consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. Per the G-GDPR , for the purposes of the UK-GDPR , the legal basis for processing data for health and social care research should not be consent. This means that requirements in the UK-GDPR relating to consent do not apply to health and care research. Per the G-GDPR , even though consent is not the legal basis for processing personal data for research, the common law duty of confidentiality still applies, so consent is still needed for people outside the care team to access and use confidential information for research.

As delineated in the UK-GDPR , the UK- DPAct , the G-GDPR , and GBR-89 , participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The UK-GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the UK-GDPR , the UK- DPAct , the G-GDPR , and GBR-89 , the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR , exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under UK-GDPR , then the PIS may need to be revised as a non-substantial amendment.

As indicated in the G-GDPR and GBR-100 , the HRA has developed a series of templates with transparency language to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study. Also see GBR-129 for guidance from the UK Information Commissioner’s Office .

Obtaining Consent

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR , the MHCTR2006 , and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ). As per the MHCTR , the MHCTR2006 , and GBR-9 , the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures ( GBR-9 ) issued by England’s Health Research Authority (HRA) .) Refer to GBR-18 and GBR-69 for more on informed consent in the UK.

The MHCTR and G-ConsentPIS , state that the investigator(s) must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant, and the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate. Per G-ConsentPIS , the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. (See the Personal Data Protection section for more information on data protection requirements.)

Per GBR-31 , the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

• The nature and the complexity of the research
• The risks, burdens, and potential benefits (to the participants and/or society)
• The ethical issues at stake

Per GBR-113 , none of the oral and written information concerning the clinical trial, including the written ICF, should contain any language that causes the participant and/or the participant’s legal representative(s) or guardian(s) to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

According to GBR-113 , the EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant and/or the legal representative(s) or guardian(s) will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per GBR-18 , during a clinical trial, researchers should periodically reaffirm the willingness of participants to continue. If significant new information becomes available, participants should be reconsented using revised (and re-approved) consent documents so that their continued consent is confirmed.

Language Requirements

As stated in the MHCTR , applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documenting Consent

The MHCTR states that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. Where the participant is illiterate, and/or the legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness. As provided in G- ConsentPIS , consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study . GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone, or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Waiver of Consent

No information is currently available.

Based on the MHCTR , the G-ConsentPIS , and International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• The study purpose, procedures, and duration
• Study title and the study Integrated Research Application System ( IRAS) ID are clearly displayed
• Approximate number of participants involved in the trial
• The participant’s responsibilities in participating in the trial
• Trial treatment schedule and the probability for random assignment to each treatment
• Experimental aspects of the study
• Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Any benefits or prorated payment to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
• A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
• Compensation and/or medical treatment available to the participant in the event of a trial-related injury
• Any additional costs to the participant that may result from participation in the research
• That participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
• The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA) , the ethics committees (ECs), the auditor(s), and the monitor(s)
• That the participant and/or the legal representative(s) or guardian(s) will be notified if significant new findings developed during the study may affect the participant's willingness to continue
• Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent

ICF examples and templates are provided in the G-ConsentPIS .

For more information about informed consent required elements, see GBR-18 , GBR-113 , GBR-100 , GBR-31 , and GBR-69 .

In accordance with the MHCTR , the MHCTR2006 , the G- ConsentPIS , and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR , the G- ConsentPIS , and GBR-113 , the participant or the legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the MHCTR , the G- ConsentPIS , and GBR-113 , a potential research participant and/or the legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

Also see GBR-117 for an interactive web-based communications toolkit to help researchers and participants keep in touch after participation in a research study.

The Right to Privacy and Confidentiality

As per the MHCTR and GBR-113 , the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

The Right of Inquiry/Appeal

The MHCTR and GBR-113 state that the research participant and/or the legal representative(s) or guardian(s) should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR , the MHCTR2006 , and GBR-113 state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

The MHCTR , the MHCTR2006-No2 , the MHCTR-BSQ , and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ) make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product (IP) is complicated by medical emergencies. As delineated in the G- ConsentPIS and GBR-18 , in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or the legal representative(s) or guardian(s) cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or the legal representative(s) or guardian(s) should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the provisions of Section 51 of the AIA2000 govern the inclusion of adults lacking capacity in research.

The G- ConsentPIS states that the United Kingdom allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

• Treatment needs to be given urgently
• It is also necessary to take urgent action to administer the drug (IP) for the purposes of the trial
• It is not reasonably practicable to obtain consent from a legal representative
• The procedure is approved by an EC
• Consent is sought from a legal representative as soon as possible

As per the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

Per GBR-131 , vulnerability may be defined in different ways and may arise as a result of being in an abusive relationship, vulnerability due to age, potential marginalization, disability, and due to disadvantageous power relationships within personal and professional roles. Participants may not be conventionally vulnerable but may be in a dependent relationship that means they can feel coerced or pressured into taking part.

As stated in GBR-131 , researchers must assess potential vulnerability within the context of the research, in terms of potential consequences from their participation (immediate and long-term) or lack of positive impact where this is immediately needed or expected. Further, researchers should make the participants aware of the limits to confidentiality and decide whether verbal or written consent will be more appropriate and protective of the participants’ interests. In addition, researchers should consider the following:

• Participants’ vulnerability
• Potential negative consequences or lack of personal benefits from their involvement in research where these are expected
• Providing appropriate information to elicit freely-given informed consent for participation as well as information regarding data deposit and data re-use (where deposit is possible)
• Limits to confidentiality and occasions where this may occur
• Legal requirements of working with the specific population
• Incentives and compensation for participation

In addition, GBR-131 states that when working with participants who are considered vulnerable, researchers may find themselves in a position of increased responsibilities or expectations. Researchers should endeavor to assess the likelihood of additional ethics issues and develop strategies and a framework of clear responsibilities they can refer to should such issues arise. They should also use their research ethics committee as a resource for advice and guidance. Researchers should be able to justify the approach they take in dealing with unforeseen ethics issues and maintain the integrity of the research.

As per GBR-131 , in cases where research involves potentially vulnerable groups, every effort should be made to secure freely given informed consent that participants have actively provided. Every effort should be made to ensure that they have the time and opportunity to access support in their decision-making, for example by discussing their choice with a trusted adult or relative. Passive assent, including group assent (with consent given by a gatekeeper) should be avoided wherever possible, and every effort should be made to develop methods of seeking consent that are appropriate to the groups studied, using expert advice, support, and training, where necessary. Vulnerability should be considered on a case-by-case basis; many groups or individuals not traditionally considered as vulnerable could be exposed to issues from participating in research that make them vulnerable. See GBR-131 for additional resources and case studies.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

According to the MHCTR and GBR-4 , a minor in the United Kingdom (UK) is an individual under 16 years of age.

As set forth in the MHCTR , the MHCTR2006 , the G-ConsentPIS , GBR-4 , GBR-9 , and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), when the research participant is a minor, informed consent should be obtained from the legal representative(s) and/or guardian(s). As per GBR-4 , the researcher needs only to obtain consent from one (1) person with parental responsibility. GBR-130 further indicates that the legal representative(s) and/or guardian(s) must not be connected with the conduct of the trial, is suitable to act by virtue of their relationship with the child/young person, and is available and willing to do so. A legal representative(s) and/or guardian(s) should only ever be approached if someone with parental responsibility cannot be contacted prior to the proposed inclusion of the child/young person due to the urgent nature of the treatment provided as part of the trial. In this situation, if a legal representative(s) or guardian(s) is not available, then a professional legal representative (e.g., a doctor) can be responsible for the medical treatment of the child/young person if they are independent of the study, or a person nominated by the healthcare provider.

Additionally, GBR-130 states that researchers must ensure that the parent(s), legal representative(s), or guardian(s):

• Understand that they are being asked to give consent on behalf of the child/young person
• Understand the objectives, risks, and inconveniences of the trial and the conditions under which it is to be conducted
• Have been informed of the right to withdraw the child/young person from the trial at any time
• Have a contact point where further information about the trial can be obtained

The MHCTR , the MHCTR2006 , and GBR-4 , state that a study may only be conducted on minors if several conditions are fulfilled including:

• An ethics committee (EC), following consultation with pediatric experts, has endorsed the protocol
• The legal representative(s) and/or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the minor from the trial at any time
• No incentives or financial inducements are given to the minor or the legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
• The trial relates directly to a condition from which the minor suffers, or is of such a nature that it can only be carried out on minors
• The participant(s) will derive some direct benefit from their participation in the trial
• The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
• The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the minor’s stage of development

GBR-4 provides additional best practices:

• Children and their parents (or those with parental responsibility) should be involved in the decision-making process around consent to take part in research, regardless of whether the child or young person is legally competent to give consent. This includes involving children or young people who are not considered competent to give consent.
• Assent should be sought from a child who is not considered competent as long as this is practicable and the child is not too young.
• In some situations, a young person who is competent may object to the involvement of their parents and their confidentiality should be respected.
• Before giving consent, children and young people should be provided with age-appropriate information that enables them to understand participation in research. Information may be provided using a layered, or staged, approach so that it is more easily understood.
• Children and young people should be given the opportunity to ask questions and to get support in their decision-making, such as talking to a trusted adult.
• Good records should be kept of any discussions about consent and of the final decision.
• Inducements and coercion must be avoided.
• Seeking consent is a process and it is good practice to engage regularly with the child and family over the course of research to confirm they are willing to continue. In studies in which children who are not competent will become competent during the study period, then consent from young people should be sought as soon as possible after competency is reached. A decision about how this will be managed should be made at the start of the study and included in the protocol.

See the MHCTR , the MHCTR2006 , GBR-4 , and GBR-9 for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet. Also see GBR-8 for a summary of changes to GBR-9 .

Assent Requirements

As indicated in GBR-4 , whenever practical and appropriate, a child's assent should be sought before including them in research. Even when a child or young person is competent, it is still normally good practice to involve the family in the decision-making process; however, if the young person objects, researchers should respect their privacy.

As per GBR-4 , for clinical trials of investigational products (IPs), it is usually inappropriate to ask very young children (e.g., under five (5) years old) to sign an assent form; however, their views should be considered. Researchers must make an informed judgment to determine when seeking assent is appropriate; the age of a child can only be taken as a guide. The child's developmental stage, knowledge of illness and experience of health care should also be considered. Although there is a danger that children can be asked to exercise greater autonomy than normal, this must be balanced with the potential loss of trust associated with denying their assent. Such judgment needs a framework of considerations for analysis, a record of observations, and discussions and a documented decision. In circumstances where seeking assent at the outset is not appropriate, the researcher could provide the child with information as and when required.

The G-ConsentPIS states that researchers must give a clear warning to potential participants when there is a risk of harm to an unborn child and/or risk when breastfeeding. The Participant Information Sheet (PIS) should provide specific advice to potential participants about the risks of becoming pregnant, of fathering a child, or of breastfeeding while taking part in the research including the need for pregnancy testing, contraceptive requirements, and how to report a pregnancy during the study. The PIS should also provide information about what will happen if a participant becomes pregnant, including whether and how the researcher will monitor the pregnancy. This would include access to the mother's and/or child's notes, and any possible follow up of the child including post-natal examinations. For men, researchers must provide clear warnings and advice if the research treatment could damage sperm and consequently pose a risk to possible pregnancies. Specific advice for pregnant partners may be needed, including information on any compensation arrangements.

Further, the G-ConsentPIS finds that the risk of harm caused during pregnancy is most likely when recruiting young people to a clinical trial for an investigational medicinal product (CTIMP). In this case, there should be consent from someone over the age of 16, and the following should be done:

• Discuss the risk of pregnancy, pregnancy testing, and the use of appropriate contraception with their parents (or the legal representative(s) and/or guardian(s)) during the consent process and with young potential participants as part of the assent process
• Consider local social beliefs
• Involve pediatricians and the ethics committee in preliminary discussions if this is a concern
• Consult young people when designing consent and writing information
• Respect the young person's autonomy but encourage involvement of the parents
• Be aware that in CTIMPs, it is the parents of children under 16 who legally provide consent, and this will include consent to pregnancy testing and discussion of contraception
• Information needs to go beyond "We will do a pregnancy test…" to include what will happen in broad terms

In accordance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section . Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

As set forth in GBR-35 , any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. According to GBR-35 , the following conditions are required for research to be conducted with this population:

• Reproductive toxicology studies have been completed and the results support conducting a trial, or there is a good reason not to conduct the reproductive toxicology studies and/or the risk of pregnancy is minimized (e.g., because she agrees to adhere to a highly effective method of contraception); Women using a hormonal contraceptive, such as “the pill,” should use an alternative method of contraception until the possibility of an interaction with the investigational product has been excluded
• The female participant is not pregnant according to her menstrual history and a pregnancy test, and is not at risk of becoming pregnant during, and for a specified interval, after the trial
• The female participant is warned about the potential risks to the developing child should she become pregnant, and she is tested for pregnancy during the trial, as appropriate
• The female is tested for pregnancy before dosing starts and possibly during the trial, as appropriate

Per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. The ethics committee must also ensure that the study will be independently monitored to assure the dignity and rights of the prisoners involved in the research.

As per the MHCTR and GBR-9 , a recognized ethics committee (EC) within the Health Research Authority (HRA) , must approve the participation of adult research participants who are incapable by reason of physical and mental capacity to give consent, and must obtain advice from professionals with expertise in handling this population.

The MHCTR and the G- ConsentPIS , specify that when a study involves adult participants with mental incapacities, informed consent should be obtained from the legal representative (s) and/or guardian(s). This consent should only be provided once the legal representative(s) or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the participant from the trial at any time. The G- ConsentPIS provides additional country-specific information on legal representative requirements.

As delineated in the MHCTR , a clinical trial of an investigational product may involve participants with mental incapacities under the following conditions:

• The participant has received information according to his/her capacity of understanding regarding the trial, its risks, and its benefits
• No incentives or financial inducements are given to the participant or the legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
• The trial relates directly to a condition from which the participant suffers, or is of such a nature that it can only be carried out on participants with mental incapacities
• The participant(s) will derive some direct benefit from their participation in the trial, or produce no risk at all
• The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the participant’s stage of development

See the MHCTR , G-ConsentPIS , and GBR-3  for detailed requirements.

As delineated in the MHCTR , the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), and GBR-9 , an investigational product (IP), referred to as an investigational medicinal product (IMP) in the United Kingdom (UK), is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

According to the MHCTR , the MHCTR2006 , the G-CTApp , and the G-GMP-GDP , the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture of any IP to be used in the trial. The sponsor or the designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in GBR-28 to obtain an MIA(IMP) from the MHRA. The MHCTR defines “manufacturing authorization” to include importing and assembly authorizations, as applicable. The G-CTApp states that if an IP is manufactured outside the European Union (EU), the clinical trial application should include an MIA(IMP), importer authorization, and qualified person (QP) declaration on good manufacturing practice (GMP) for each site. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

As per the MHCTR , the MHCTR2006 , the G-GMP-GDP , and GBR-15 , and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the MIA(IMP) holder must also comply with the GMP guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR and the MHCTR2006 specify that the holder of an MIA(IMP) must always have the services of at least one (1) QP at his/her disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to use in a clinical trial, or prior to release for sale and placement in the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

In accordance with the G-ImportIMPs , IPs that have been QP-certified in countries on the list of approved countries (initially, EU and European Economic Area (EEA) countries per G-CTApprovedCountries ) do not need to be re-certified when importing to the UK. However, the sponsor must require the MIA(IMP) holder to put in place an assurance system to check these IMPs have been certified by a QP in a listed country before release to the trial. A sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP). IPs coming to Great Britain from Northern Ireland do not require this additional oversight. IPs coming directly to the UK from third-party countries that are not on the list of approved countries will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements. See the G-ImportIMPsAuth , for additional details on the authorizations and procedures. For additional details on what is new from Brexit, see the Scope of Assessment section .

The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119 .

Per the G-SubtlAmndmt , for any change to IP manufacturing, importation, or certification relevant to the supply of IPs in an ongoing UK trial, a substantial amendment must be submitted to the MHRA. However, if the sponsor chooses to retain an existing UK release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only, then no substantial amendment to the MHRA will be required.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing ( GBR-5 ), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48 .

Investigator’s Brochure

In accordance with the MHCTR , the MHCTR2006 , and GBR-92 , the sponsor or the designated representative is responsible for providing investigators with an Investigator’s Brochure (IB), which must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or the designated representative should also update the IB as significant new information becomes available.

As specified in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the IB must provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IPs in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
• Summary of data and guidance for the investigator(s)
• Bibliography

See Section 7 of GBR-113 for detailed content guidelines.

Quality Documentation

Per GBR-113 , the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR , the MHCTR2006 , GBR-15 , the EU Good Manufacturing Practice Directive ( GBR-12 ), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ). Per GBR-12 , labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in GBR-15 , for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in GBR-15 , the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

• Name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator
• Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/concentration
• Batch and/or code number to identify the contents and packaging operation
• Trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
• Trial participant identification number/treatment number and where relevant, the visit number
• Investigator name (if not already included above)
• Instructions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
• “For clinical trial use only” or similar wording indicating the IP is clinical trial material
• Storage conditions
• Expiration date (use by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
• “Keep Out of Reach of Children” except when the product is not going to be taken home by participants

As per the MHCTR , a sample of the labeling is required as part of the clinical trial application submission. (See the Submission Content section for detailed clinical trial application submission requirements). Furthermore, according to GBR-15 , the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Supply, Storage, and Handling Requirements

As defined in the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) ( GBR-113 ), the sponsor must supply the investigator(s)/institution(s) with the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

Per the MHCTR and GBR-113 , the sponsor must ensure the following: (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.)

• IP product quality and stability over the period of use
• IP manufactured according to good manufacturing practice guidance ( G-GMP-GDP and GBR-15 )
• Proper coding, packaging, and labeling of the IP(s)
• IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
• Acceptable storage temperatures, conditions, and times for the IP
• Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
• Timely delivery of the IP(s)
• Establishment of management and filing systems for the IPs
• Sufficient quantities of the IP for the trial

As delineated in GBR-15 , IPs should remain under the control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person (QP) and release by the sponsor for use in a clinical trial. Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. De-coding arrangements should be available to the appropriate responsible personnel before IPs are shipped to the investigator site. A detailed inventory of the shipments made by the manufacturer or importer should be maintained and include the addressees’ identification.

Refer to the MHCTR and GBR-113 for detailed, sponsor-related IP requirements.

To help ensure the continuity of supply of medicines for clinical trials from January 1, 2021, the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain European Union (EU) regulatory processes for a time-limited period. This recognition is known as “standstill.”

Record Requirements

As per GBR-113 , the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related pharmacy records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics.

As set forth in GBR-113 , sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006 , the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

The term “specimen” is not referenced within the United Kingdom (UK). However, the following terms are used relating to specimens:

• Relevant material: As per the UK-HTA , Code-E , GBR-73 , and GBR-76 , “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
• Bodily material: UK-HTA and GBR-64 defines “bodily material” as material from a human body that consists of, or includes, human cells. Unlike relevant material, this includes gametes, embryos outside the human body, and hair and nails from the body.
• Tissue: GBR-64 defines “tissue” as any human material (e.g., blood, biopsies, urine) and includes relevant and bodily material.

Import/Export

As specified in the UK-HTA , the Human Tissue Authority (HTA) has jurisdiction regarding the import and export of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) and complies with the Code of Practice on import and export set forth in Code-E . According to the UK-HTA , Code-E , GBR-56 , GBR-73 , and GBR-52 , the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA . However, once the material is imported, storage of this material may be licensable unless it is for a specific research project with ethical approval from an ethics committee (EC). GBR-73 explains that it is preferable for imported human tissue to be stored in a licensed establishment where possible, and if so, there is no requirement for EC approval to undertake research. However, if the premises where the human tissue will be held are not covered by a HTA license, each research project using the human tissue will require EC approval.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third-party agreement with an establishment licensed by the HTA to store material for human application. See G-Tissues-Brexit for guidance on Brexit-related regulatory changes that apply to the movement of human tissues and cells between Great Britain, Northern Ireland, and Europe. Establishments importing or exporting human tissues and cells intended for human application may require an HTA license covering these activities. For additional help, clinical trial staff should contact the HTA at [email protected]. For more information about Brexit, see the Scope of Assessment section .

Code-E requires imported and exported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in Code-E . Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales, or Northern Ireland must comply with the guidelines set forth in Code-E . For exports, donors should be provided with adequate information upon providing consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

In addition, the G-QualityBlood lists the quality and safety standards when importing or exporting blood into or from the EU/European Economic Area (EEA). The UK maintains the existing quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components. The Medicines and Healthcare Products Regulatory Agency (MHRA) should be consulted before importing or exporting blood or blood components. See the G-QualityBlood for relevant EU quality and safety directives.

Other Considerations

As set forth in the UK-HTA , the HTRegs , and GBR-9 , the HTA also regulates the storage and use of specimens from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Per GBR-9 , the HTA and the Health Research Authority (HRA) have agreed to collaborative arrangements in a Memorandum of Understanding. See GBR-8 for a summary of changes to GBR-9 .

Note that per GBR-9 and GBR-105 , an HTA license is not needed for the storage of specimens for certain research projects that have been approved by an ethics committee (EC). The HTA and the UK Health Departments’ Research Ethics Service (RES) ( GBR-62 ) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

Per the UK-HTA , the G-QAHumTissue , and Code-E , the scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research. Per GBR-52 , the Scotland-HTA does not regulate the use of tissue from the living for research.

In accordance with the UK-HTA , Code-A , GBR-59 , and GBR-9 , prior to collecting, storing, or using a research participant’s specimens (known as relevant material/human tissue in the United Kingdom (UK)), consent from the participant and/or the legal representative(s) and ethics committee (EC) approval must be obtained. The scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research.

Per G-ConsentPIS , the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. As delineated in the UK-GDPR and UK-DPAct , personal data includes genetic data and biological samples. G-GDPR indicates that for the purposes of the UK-GDPR , the legal basis for processing data for health and social care research should not be consent. This means that requirements in UK-GDPR relating to consent do not apply to health and care research, and therefore, do not change the consent requirements to participate in a clinical trial and remove human tissue samples. For more information about the sponsor and investigator’s responsibilities to comply with the data protection requirements (e.g., transparency, safeguards, and data rights), see the Sponsorship topic .

Human Genetic Research Consent Requirements

As set forth in the UK-HTA , GBR-9 , and GBR-37 , the UK-HTA considers it a UK-wide offense to have relevant material/human tissue with the intention of conducting a DNA analysis or using the results of this analysis without “qualifying consent” from a participant and/or the legal representative(s), unless the information is being used for an “excepted purpose.” The UK-HTA states that “qualifying consent” is consent required in relation to the analysis of DNA manufactured by the human body. An “excepted purpose” is defined as the following:

• Medical diagnosis/treatment
• Coroner purposes
• Crime prevention/detection
• Prosecution
• National security
• Court/tribunal order
• An existing holding to be used for research

In addition to participant consent, EC approval is required for the analysis of DNA in material from the living, where the research is not within the terms of consent for research from the person whose body manufactured the DNA. Please refer to the UK-HTA , GBR-9 , GBR-37 , and GBR-75 for detailed DNA analysis consent requirements.

Donor Consent Requirements

In accordance with the UK-HTA , Code-A , and GBR-9 , prior to removing, storing, or using any living or deceased person’s organs, tissues, or cells for the purpose of research in connection with disorders in, or the functioning of the human body, investigators must obtain “appropriate consent” from the trial participants and/or their legal representative(s) as well as EC approval. The UK-HTA and Code-A define “appropriate consent” in terms of the person who may give consent. This person may be either the trial participant, the legal representative (referred to as “nominated representative” in the UK-HTA ), or, in the absence of either of these, the consent of a person in a “qualifying relationship” with the participant immediately before he/she dies.

As indicated in the UK-HTA and Code-A , in the case of a living child donor, “appropriate consent” must be obtained from the child’s legal representative(s) and/or guardian(s. If the child has died, the written consent must have been obtained from the child’s legal representative(s) and/or guardian(s) prior to the child’s death in the presence of at least one (1) witness, or it must be signed at the direction of the child concerned by the legal representative(s) and/or guardian(s), in the child’s presence, and in the presence of at least one (1) witness.

As indicated in the UK-HTA and Code-A , in the case of an adult donor, 18 years or older, consent must be obtained prior to removing any bodily materials. If the adult has died, the written consent is only valid when it is signed by the person prior to death in the presence of at least one (1) witness at his/her direction, or it is contained in the person’s will. An adult donor may also appoint one (1) or more people (“nominated representative(s)”) to consent on his/her behalf in the event of death. This consent may be obtained orally or in writing. If the deceased donor has neither provided consent nor an appointed or nominated representative, appropriate consent may be given by someone in a “qualifying relationship” with the donor immediately prior to death. Refer to the UK-HTA and Code-A to obtain a complete list of relatives in hierarchical order who may qualify to provide this consent.

In the case of obtaining materials from an adult donor who lacks the capacity to consent, and neither a decision to consent or not consent is in force, the UK-HTA , the MCA2005 , GBR-9 , and GBR-37 state that approval by an EC is required. In addition, a living person’s organs, tissues, or cells may be stored and used without consent if the investigator is unable to identify the individual and it is being used for an EC-approved research project. Please refer to the UK-HTA and Code-A for detailed consent requirements.

Per GBR-59 , the legal exemptions to consent for research with relevant material are as follows:

• The relevant material is an existing holding held prior to September 1, 2006
• The relevant material is imported
• The relevant material is from a living person when the sample was taken, is non-identifiable, and will be used in research with/pending project-specific EC approval
• The relevant material is from a person who died more than 100 years ago

See the Required Elements and Participant Rights sections for additional information on informed consent.

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Clinical Trial Site Management

Covering the All-Round Management of Clinical Trial Sites

We offer site management services in Central and Eastern European (CEE) countries to companies intending to conduct clinical trials in this region. Our unique combination of being based in the UK, a global hub and centre of excellence in clinical research, and having intimate local knowledge and understanding of clinical trial operations in Central and Eastern Europe, make us an ideal partner for companies intending to conduct clinical trials in this region. Our offering in this area is aimed at small and medium sized pharmaceutical and biotech companies looking for assistance and a like-minded partner with an ethos of treating every client special and providing bespoke site management services as opposed to the “one-size-fits-all” approach associated with large site-management-organisations.

The availability of willing patients, very experienced researchers and EMA-compliant legislation make the CEE region an attractive clinical trial site destination. The general feedback continues to suggest that the high productivity of CEE sites is accompanied by regulatory compliance and data quality standards that match those in Western regions.

Our streamlined and integrated site management services are delivered by a dedicated network of professionals with industry and therapeutic area expertise across all phases of clinical development. This, coupled with our in-depth understanding of operations in the CEE countries and strong relationships with trial sites, results in an efficient and effective trial start and recruitment of patients to achieve your goals.

Stridon’s clinical site management services include:

• Site selection and feasibility
• Site contract and budget management
• Preparation of site specific documentation
• Ethics Committee and Regulatory submissions
• Subject recruitment and retention management
• Generic and study specific training for clinical trial staff
• Coordination of clinical trial medication supplies
• Clinical trial monitoring
• Assurance of good clinical practice
• Site communication strategy and progress reporting
• Subject safety management
• Third party vendor management

Additional services may be included depending on the client’s needs, providing assistance in preparing sites for clinical trials and ensuring that logistical, regulatory and ethical requirements are met. Such other services may include site Standard Operating Procedure (SOP) writing, arranging for Case Report Form (CRF) development and data management services, organising laboratory sample analyses and documentation archiving.

Our operational personnel is field based throughout the CEE region, not only to limit travel and support the project team, but primarily to leverage local knowledge of the clinical research and regulatory environments. They focus on developing strong site relationships while ensuring the site’s adherence to data quality, subject safety and early issue resolution throughout the course of the trial.

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Velocity Opens Three UK Greenfield Clinical Research Sites

Velocity Clinical Research, the leading multi-specialty clinical sites business, announced it is opening greenfield clinical research sites in Bristol, Leicester, and Romford, demonstrating the company’s commitment to the U.K. market. 

The sites launch at a time when clinical trial activity in the U.K. has fallen in recent years. The number of patients enrolled in commercial clinical trials in the U.K. has decreased by 44% between 2017-18 and 2021-22.

Velocity’s growth is accelerating in the UK and Europe, with nine sites in total. The three new sites in the UK join Velocity’s two existing locations in High Wycombe and North Finchley, and four in Germany. Velocity, to date, has grown via site acquisition. However, it is setting up its own sites in the U.K., demonstrating its commitment to the Sponsors and CROs who need to conduct clinical trials here. 

Dominic Clavell, European General Manager for Velocity, said, “Velocity’s people know how to run sites. Traditionally, clinical trials in the U.K. have been dominated by the NHS and University-based research, but with funding pressures and the continuing toll of COVID on these institutions, we believe private organisations like Velocity are an alternative solution to deliver faster start up, greater efficiency, and quicker data delivery. We are reaching a critical mass in the UK and Europe, which is important for how we care for patients and work with Sponsors.”

Velocity Romford started training staff in August 2023, will enrol patients into studies this month, and will be headed by Shilpa Muthusamy, MD. Both Velocity Bristol and Velocity Leicester expect to start enrolling patients at the end of October. The latter site will be led by Matt Fisher, MD. Velocity will announce the Principal Investigator of Bristol’s site in due course.

Shilpa Muthusamy, MD is an experienced clinical research physician, and holds a Bachelor of Medicine and Bachelor of Surgery from the University of Nottingham. Dr. Muthusamy has worked as an Investigator, managing Phase 2-4 clinical trials across a wide range of therapeutic areas and indications, including neurology, chronic pain, Alzheimer’s disease, rare conditions, and psychiatry. Prior to her career in clinical research, Dr. Muthusamy specialised in anaesthesia and intensive care. She brings with her an extensive knowledge of pharmacology and physiology.

Dr. Muthusamy, Velocity Principal Investigator said, “I have worked with complex patients, led teams in fast-paced environments, and provided meticulous attention to detail, which I look forward to applying to clinical research. I am passionate about promoting diversity within clinical trials and continuing to provide the best possible outcomes and care for every patient.”

Matt Fisher, MD qualified from Bristol Medical School in 2015 and worked as a doctor in general and emergency medicine for five years in the NHS. During this period, he also completed a Graduate Diploma in Law and was an NHS Innovation Fellow. Dr Fisher started in clinical development roughly four years ago and has worked for both a CRO and a Sponsor. He has led clinical trials in ATTR Amyloidosis from Phase 1-3 for CROs and was involved with regulatory submissions, protocol development, and early stage clinical development strategy at Sponsor level.

Dr. Fisher, Velocity Principal Investigator, commented, “My experience working at Sponsor and CRO level and in Phase 1 trials will be influential for the Phase 3-4 research as the lessons of safety and dosing that are learnt, pave the path to efficacy and regulatory approval. The research I have conducted so far covers a plethora of innovative therapeutic areas, from gene therapy to CRISPR technology and I look forward to diversifying this expertise at Velocity.”

Velocity has over 80 locations globally and access to more than 220 principal investigators and one million patients. Velocity’s sites are fully integrated via a centralised infrastructure and common technology backbone, allowing for superior patient enrollment and consistent, high-quality data delivery. As a result, CROs and biopharma companies can benefit from simplified access to international clinical research.

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Help us advance world medicine

Find a clinical trial near you, browse therapy areas, proud to be the patient’s choice for clinical research.

Dedicated to conducting clinical trials, Synexus have been investigating the effectiveness of new medicines and treatments for more than 25 years. We have vast experience in conducting clinical research with 7 clinics in the UK and approaching 200 sites around the world. Each has its own dedicated team of highly trained doctors and nurses to provide our patients with the highest level of comfort and professionalism.

Whether discussing your progress over a cup of tea or enjoying complimentary snacks after fasting for a blood sample, these personal touches make Synexus clinics such a welcoming place for you to take part in a clinical trial.

Bones & Joints

Bones and joints are part of our musculoskeletal system and they provide the framework for the body to move. Bones and joints may be affected by painful conditions such as arthritis, osteoporosis, tendonitis and rheumatoid arthritis.

The most common condition affecting bones is osteoporosis which is caused by a reduction in bone mass. Losing bone mass is a natural part of aging however it may be excessive in some people who end up developing osteoporosis. This means your bones become weak and are more likely to have fractures and damage.

We regularly conduct clinical trials into osteoporosis or studies evaluating the risk of developing osteoporosis, as well as clinical trials for arthritis. Our state of the art DEXA scanning machines help with the accurate diagnosis of osteoporosis and monitoring of patients who are at risk of developing osteoporosis.

Chronic Pain

Pain is a severe sensory experience which may affect any part of the body. It may be acute pain which lasts for a short period of time but is often severe such as headaches, or it may be chronic (or persistent) pain which lasts for weeks, months or even years such as back pain. Chronic or persistent pain is defined as pain that has lasted for longer than three months after the usual recovery period for an illness or injury.

We regularly conduct clinical trials into chronic pain treatment which includes conditions such as headache and migraine, back, shoulder, knee or neck pain. We also conduct studies in pain related to post dental surgery, shingles (herpetic neuralgia) and diabetes as well as pain that occurs after an injury or operation.

Diabetes mellitus is a condition in which your blood sugar levels are too high because the body cannot control the level properly. Insulin is a hormone that is produced by the pancreas and lowers blood sugar by helping the sugar (glucose) to move into your body cells which use it as a source of energy.

There are different types of diabetes: Type I diabetes occurs when your pancreas does not make any insulin and may be diagnosed in childhood or early teens. Type 2 diabetes occurs when your pancreas is unable to make enough insulin or it no longer works effectively to reduce blood sugar levels. High levels of blood sugar can cause serious problems which may damage your eyes, kidneys, and nerves.

We regularly conduct clinical trials involving Type2 diabetes to reduce the blood sugar levels, reduce the risk of heart attacks and strokes and problems that can arise as a result of high blood sugar levels.

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Problems affecting the digestion and bowel are very common and may cause severe pain, weight loss, change in bowel motion and abdominal discomfort. The most common digestive problems such as heartburn, reflux, peptic ulcers, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) cause daily suffering for millions and can limit a person’s quality of life.

We regularly conduct clinical trials for conditions such as reflux, indigestion, peptic ulcers, constipation, diarrhoea and irritable bowel syndrome.

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The endocrine system is a network of glands that produce and release hormones. Hormones are chemical messengers that travel through your bloodstream to tissues and organs. Hormones help to control many important bodily functions and affect nearly every cell and organ in the body. They affect the body’s ability to produce the energy that is needed to power cells, they stimulate cell growth and development, affect your mood, strengthen bones, influence sexual functions and control your metabolism. There are many different types of hormone disorders and diabetes is an example of an imbalance in insulin.

We regularly conduct clinical trials for conditions such as diabetes, as well as studies into obesity, osteoporosis, high cholesterol and lipids, and other metabolic disorders.

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The heart and circulatory system delivers blood to every cell in our body through a network of blood vessels. Problems to the blood vessels are common and can result in high blood pressure, poor circulation (peripheral arterial disease), atherosclerosis which is where the wall of the artery becomes thickened.

The most common cause of heart disease is narrowing or blockage of the coronary arteries, the blood vessels that supply blood to the heart itself and is the reason that most people have a heart attack. You are more likely to have problems with your blood vessels as you get older.

We regularly conduct clinical trials for conditions such as high cholesterol, high blood pressure and diseases that put you at a greater risk of having a heart attack/stoke or a recurrence of these events. We will normally conduct an evaluation of your lipid profile as part of a cardiovascular study evaluation.

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The human body has numerous mechanisms to fight infection. The immune response is how your body recognizes and defends itself against bacteria, viruses, and substances that appear foreign and harmful. In most cases, the immune response will keep you healthy and will prevent infections. But sometimes problems with the immune system can lead to infections, allergies or diseases such as Lupus.

To help prevent infection scientists have developed many vaccines for specific diseases such as whooping cough, measles and polio. Vaccines work by stimulating our immune system to produce antibodies (substances produced by the body to fight disease) without actually infecting us with the disease. This helps to prevent us from getting the infection in future.

We regularly conduct clinical trials for allergy as well as vaccine studies for the prevention of many diseases.

We regularly conduct research studies relating to lifestyle and habit, such as weight management, smoking cessation, nutritional supplements.

Many of our studies involve ongoing support in relation to diet, counselling, and exercise.

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Your brain stores information and when you remember something, you pull the information from your memory. But your memory doesn’t always work perfectly. As people grow older it may take longer to remember something and it is normal to forget things. Older people who become more forgetful than others of their age may have “mild cognitive impairment”.

Forgetting how to use the telephone or find your way home may be signs of a more serious problem, such as Alzheimer’s disease or other types of dementia, stroke, depression, head injuries, thyroid problems, or reactions to certain medicines.

We regularly conduct clinical trials into cognitive changes (trouble remembering, learning new things, concentrating, or making decisions), sleep disturbances, dementia, addiction and mental and emotional health issues such as depression. We will normally conduct an evaluation of your memory as part of our memory study evaluation.

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Reproduction is the process by which people have children. There are many conditions which may affect the male reproductive system and that may be part of a Synexus clinical trial including erectile dysfunction, contraception, sexually transmitted diseases, and conditions affecting the prostate gland such as an enlarged prostate gland and screening for prostate cancer.

Disease and conditions that affect the female reproductive system or women’s health include contraception, menstruation, and post-menopausal conditions and sexually transmitted diseases.

We regularly conduct clinical trials for female sexual dysfunction, menstrual and post menopause-related conditions as well as many aspects of women’s health.

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Breathing is controlled by the respiratory system and when you breathe you take in oxygen and get rid of carbon dioxide. Many conditions related to the health of your lungs can result in shortness of breath, chronic coughing or breathing difficulties. The short term problems are usually caused by infections, such as colds and flu but long term breathing problems may be due to medical conditions such as allergies, asthma and COPD.

We regularly conduct clinical trials into breathing problems such as Asthma and COPD as well as treatments for smoking cessation and flu vaccinations. We routinely use spirometry tests (breathing tests) to determine how well your lung is functioning as part of the assessment before you participate in a study.

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Your skin is your body’s largest organ its role is to cover and protect your body.

As well as covering for your internal organs, your skin helps you to feel the external environment, for example, hot, cold and pain and is important in making vitamin D when the sun shines. Anything that irritates, clog or inflames the skin can cause symptoms such as redness, swelling, burning or itching. In addition, you can get allergic reactions that show themselves as rashes or other skin conditions. There are many different skin disorders. Some are short term, easily treated, and just a nuisance. Others can persist for a long time and be troublesome and many skin problems, such as acne or atopic dermatitis (eczema) affect your appearance.

We regularly conduct clinical trials into skin conditions, including atopic dermatitis (eczema), acne, rosacea, and psoriasis.

What’s involved?

Our informed consent process is designed to help give you all the information that you need as well as an opportunity to ask questions and decide what is right for you.

Our team will talk through your current health and advise you about any clinical trial you might be suitable for. If you want to go ahead, we will arrange a consultation at one of our clinics to give you full study details to take away and discuss with your family before you make a decision.

You’ll be joining a growing community of over 14,000 Synexus volunteers.

Our highly trained doctors and nurses provide an advanced level of comfort and care.

You will receive a free health check and be contributing to the health of future generations.

We can help with transport to and from our clinics or reimburse for reasonable travel expenses.

How do I take part?

We have put together a guide to help you better understand our clinical trials and determine whether they are the right option for you.

Refer a friend

If you know somebody who may be suitable for a clinical trial, please recommend them to Synexus and you’ll receive £100 as a thank you when they enrol on a study.

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Academic recognised in the Research.com Ranking of Best Scientists

UCL academic, Patrick Royston, has been recognised on the Research.com Ranking of Best Scientists.

Patrick Royston, Emeritus Professor of Statistics at the MRC Clinical Trials Unit at UCL, has been named in the 2024 Research.com Ranking of Best Scientists in the field of Mathematics.   Patrick is ranked #89 in the world and #4 in the UK. He was also recognised with the Mathematics Leader Award for 2024.   Patrick spent most of his working life researching statistical methods in medicine and allied disciplines. His main interests centred on statistical modelling and its applications in medicine, with a special interest in cancer clinical trials. He joined the MRC CTU at UCL in 2000 and worked on a number of cancer trials and methodology projects before retiring in 2023.   Now in an emeritus professor role, Patrick continues to contribute to the MRC CTU at UCL’s work on trial design and analysis, including a project on flexible parametric models in survival analysis.   Learn more about Patrick Royston on the MRC CTU at UCL website and find the full  UK rankings on Research.com.  

Related News

A systematic analysis of the contribution of genetics to multimorbidity and comparisons with primary care data

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Background Multimorbidity, the presence of two or more conditions in one person, is increasingly prevalent. Yet shared biological mechanisms of specific pairs of conditions often remain poorly understood. We address this gap by integrating large-scale primary care and genetic data to elucidate potential causes of multimorbidity.

Methods We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large representative healthcare databases [CPRD (UK) N=2,425,014 and SIDIAP (Spain) N=1,053,640], and estimated heritability using the same definitions in UK Biobank (N=451,197). We used logistic regression models to estimate the co-occurrence of pairs of conditions in the primary care data.

Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across healthcare databases, and up to three sources of genetic data, for each condition pair. We classified pairs of conditions as across or within-domain based on the international classification of disease.

Findings We identified N=72 chronic conditions, with 43·6% of 2546 pairs showing higher co-occurrence than expected and evidence of shared genetics. Notably, across-domain pairs like iron deficiency anaemia and peripheral arterial disease exhibited substantial shared genetics (genetic correlation R g =0·45[95% Confidence Intervals 0·27:0·64]). N=33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis ( R g =-0·14[-0·21:-0·06]), indicating potential protective mechanisms. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred but were not genetically correlated (Odds-Ratio=2·23[2·09:2·37], R g =0·04[-0·20:0·28]) and schizophrenia and fibromyalgia were less likely to co-occur but were positively genetically correlated (OR=0·84[0·75:0·94], R g =0·20[0·11:0·29]).

Interpretation Most pairs of chronic conditions show evidence of shared genetics and co-occurrence in primary care, suggesting shared mechanisms. The identified shared mechanisms, negative correlations and discordance between genetic and observational data provide a foundation for future research on prevention and treatment of multimorbidity.

Funding UK Medical Research Council [MR/W014548/1].

Competing Interest Statement

ARL is now an employee of AstraZeneca and has interests in the company. The work undertaken here was prior to his appointment. SK's group has received funding support from Amgen BioPharma outside of this work. JB is a part time employee of Novo Nordisk Research Centre Oxford, limited, unrelated to this work. TF has consulted for several pharmaceutical companies. All other authors have no disclosures to declare.

Funding Statement

This work was supported by the UK Medical Research Council [grant number MR/W014548/1]. This study was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC), the NIHR Leicester BRC, the NIHR Oxford BRC, the NIHR Peninsula Applied Research Collaboration, and the NIHR HealthTech Research Centre. KB is partly funded by the NIHR Applied Research Collaboration South-West Peninsula. JM is funded by an NIHR Advanced Fellowship (NIHR302270). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. CV acknowledges research funding by a "Contratos para la intensificacion de la actividad investigadora en el Sistema Nacional de Salud" contract (INT23/00040) from the Spanish Ministry of Science and Innovation.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the relevant ethics committees: SIDIAP Scientific and Ethical Committees (19/518-P) on 18/12/2019. The SIDIAP database is based on opt-out presumed consent. If a patient decides to opt out, their routine data would be excluded of the database. CPRD ISAC committee protocol number 23_003109. The Northwest Multi-Centre Research Ethics Committee approved the collection and use of UK Biobank data for health-related research (Research Ethics Committee reference 11/NW/0382). UKB was granted under Application Number 9072.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

↵ * = joint first authors

↵ # = joint senior authors

Data Availability

We cannot make individual-level data available. Researchers can apply to UK Biobank ( https://www.ukbiobank.ac.uk/enable-your-research/ ), CPRD ( https://www.cprd.com/research-applications ), and SIDIAP ( https://www.sidiap.org/index.php/en/solicituds-en ). We have made our diagnostic code lists, code and results available on our GitHub ( https://github.com/GEMINI-multimorbidity/ ) site and Shiny website ( https://gemini-multimorbidity.shinyapps.io/atlas/ ). GWAS summary statistics will be available following acceptance at the GWAS Catalog ( https://www.ebi.ac.uk/gwas/home ).

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