Our full response to WHO consultation on improving clinical trials

1. Who we are

The HRA was established in December 2011 in England to protect and promote the interests of patients and the public in health and social care research. Our vision is for high quality health and social care research today, which improves everyone’s health and wellbeing tomorrow. We help realise this by making it easy to do research that people can trust.

We are one of a number organisations that work together in the UK to regulate different aspects of health and social care research. Most of our functions apply to research undertaken in England, but we also work closely with the other countries in the UK to provide a UK-wide system.

2. The HRA’s three-year strategy

Over the next three years the HRA’s focus will be on earning and maintaining people’s trust in research. By working in a balanced and proportionate way we will make it simple and fast to deliver research that people can trust. Our strategy sets out two main principles that guide our work – include and accelerate – and how we will make these happen – using digital technology well and always looking for ways to do things better.

2.1. INCLUDE

Health and social care research is done with and for everyone. Meaningfully involving people in all stages of research and sharing its findings is crucial to earn people’s trust. It helps us do better research that can improve care.

The HRA will:

• push for change to increase diversity and inclusion in research
• increase public involvement in research
• make transparency the norm for research

We will:

• ask what patients and the public want research to look like and act on this
• ask what patients and the public want research to look like and act on this
• champion issues that are important to people in research
• create public conversations about research issues that matter to people
• encourage researchers to do a better job of putting people first
• increase public involvement in how we make decisions
• listen to and involve a diverse group of people in our work
• talk in a way that everyone can access and understand

2.2. ACCELERATE

Save money and time so that researchers can focus on doing good research.

To earn people’s trust, research projects involving people, their tissue or their data need a number of approvals before they can go ahead. We will make it easier for researchers to find out what they need to do and earn these approvals.

We will:

• join up research approvals across the UK
• make it easier to put people first in research
• support action to ensure that precious NHS resources are focussed on research that will help improve care

Create a new online system to help you make research happen

The approvals that each research project needs come from different organisations depending on what it is trying to do. We will:

• connect the steps that are part of doing research and make them easy to follow
• work with others so that each step taken informs the next

Support new ways to do research

We will make it possible to do new types of research here in the UK so that we can get better, quicker answers and put people first.

We will:

• work with research teams to explore new ways to do research and make these happen
• learn together to make sure that regulation keeps up with research so our decisions can be trusted

3. Our response

The HRA welcomes and supports the WHA Resolution 75.8 and are grateful for the opportunity to comment on this current Stakeholder Consultation. Rather than comment on all aspects of the consultation via the online form we are submitting this response highlighting the work we (as a regulator of health and social care research conducted within the NHS) and our partners are currently involved with to strengthen the clinical trials ecosystem in the UK.

Our response below sets out the details of several initiatives which fall within the following consultation question areas:

• strengthening the global, regional, or national clinical trials ecosystems (Consultation Q.2)
• reducing research waste (Consultation Q.5)
• digitization/paperless approaches to clinical trials (Consultation Q.7)
• addressing insufficient representation of specific population segments in clinical trials (Consultation Q. 8)
• efficient adaptation and deployment of capacities during Public Health Emergencies of International Concern (PHEIC) (Consultation Q.15)

4. Summary of HRA response areas to relevant WHO consultation questions

Q.2, Q.5, Q.8 Revisions to the UK clinical trials legislation

Following consultation, the MHRA, the HRA and the Northern Ireland Department of Health will be revising the UK Clinical Trials Regulations to develop a system which:

• embeds a flexible and proportionate approach to clinical trials
• promotes patient and public involvement
• improves inclusion and diversity of participants
• streamlines clinical trial approvals

Q.2 Combined review

Regulatory review by the Medicines and Healthcare products Regulatory Agency and ethics reviews by the UK Research Ethics Service are conducted in parallel with requests for further information raised jointly resulting in a single decision from both reviews.

Q.5 Research transparency

Automatic registration: The HRA automatically register clinical trials approved through combined review with the ISRCTN registry. If a trial is registered with ClinicalTrials.gov the applicant can request not to be registered on the ISRCTN Registry.

Communicating results to participants: Updating guidance to ensure that research findings are communicated to participants appropriately and that research participants feel valued.

Final reports: Standard final reports make it easier to report on and measure transparency across research.

Q.5 Public involvement

Shared Commitment: The HRA, the National Institute for Health Research and a host of organisations across the UK have signed up to a Shared Commitment to embedding public involvement in health and social care research.

Information and consent documentation: New tools and guidance for applicants and research ethics committee members for designing, and for evaluating, the design of information and consent documentation and processes which will clarify how the involvement and input of public contributors will be taken into account in ethics review.

Q15 Expedited procedures for rapidly implementing clinical trials during PHEIC

During the COVID-19 pandemic the HRA and the devolved administrations:

• developed a fast-track review process to review studies for certain types COVID-19 research, such as vaccine studies, and amendments to existing studies, often within a few days of application
• implemented a fast-track transparency process, in which information about each approved COVID-19 study was published on ourresearch summaries website within days of approval
• During the pandemic a temporary general COPI notice was issued by the Secretary of State for Health and Social Care, which provided a common law legal basis to process confidential patient information without consent for COVID-19 public health, surveillance and research purposes in England and Wales

Current HRA activity to strengthen the UK clinical trials ecosystem

The HRA, in partnership across the UK, between regulators, other agencies, the research community, and above all with people, are currently taking forward several campaigns to strengthen the clinical trials ecosystem in the UK and in doing so deliver on our vision for high quality health and social care research today, which improves everyone’s health and wellbeing tomorrow.

4.1. Revisions to the UK Clinical trials legislation

The MHRA, the HRA and the Northern Ireland Department of Health have recently consulted on new proposals to capitalise on the opportunity provided by the UK’s exit from the European Union to improve the regulation of clinical trials in the best interests of patients in line with the ambitions of the UK government and the life science sector’s Life Sciences Vision. The proposals, which were publicly consulted on from 17 January to 14 March 2022, aim to develop a system which embeds a flexible and proportionate approach to clinical trials, promotes patient and public involvement, improves the diversity of participants and streamlines clinical trial approvals.

The consultation set out proposals to amend the current legislation to:

• ensure patients and their safety are at the focus of all clinical trials and bring the benefits of clinical trials to everyone
• create a proportionate and flexible regulatory environment
• remove obstacles to innovation, whilst maintaining robust oversight of the safety of trials
• provide a framework that is streamlined, agile and responsive to innovation
• streamline the regulation of clinical trials and reduce unnecessary burden to those running trials by taking a risk-based approach
• ensure the legislation enables trial sponsors to work across countries so that the UK remains a preferred site to conduct multi-national trials

The Government Response will be published shortly. All responses have now been carefully reviewed and will inform decisions to finalise the drafting of the secondary legislation that will amend the current legislation.

4.2. Combined review

One example of the way we are working with our partners to join up research approvals across the UK is combined review. This is the way research teams seek approval for new Clinical Trials of Investigational Medicinal Products (CTIMPs) and combined medicine and device trials. Research teams are now able to make a single application which goes to both the Medicines and Healthcare products Regulatory Agency (MHRA) and a research ethics committee (REC) 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. Combined review with the MHRA is on average twice as quick as two separate systems were1.

4.3. Streamlining the research ecosystem

We are drawing this streamlining together as part of a UK approval system supported by developments in IRAS (the Integrated Research Application System), where researchers and companies are guided along an ideal path to provide the right information to the right place at the right time.

4.4. Recovery, Resilience and Growth Programme

Through the Recovery, Resilience and Growth Programme we seek to better understand and remedy immediate system issues but also those underpinning systemic root causes that might be preventing quicker or more impactful progress. The HRA is working with others to improve clinical research delivery to time and target by identifying and removing barriers caused by governance arrangements or policy. One example is our updated guidance with Medicines and Healthcare products Regulatory Agency (MHRA) on remote monitoring of electronic health records.

4.5. Model agreements

Study set-up in the NHS is being streamlined through our expanding suite of model agreements and the reviving of the National Contract Value Review – transparent up-front prices from NHS organisations and a single negotiation. We are sponsoring a project with the Experimental Cancer Medicine Centres to explore radical new ways to set-up early phase cancer studies in the NHS.

4.6. Digitising the clinical research process

We are also addressing areas where there is untapped potential. With our expertise in information governance, we’re advising on the development of a Find, Recruit and Follow-up service, which will use a suite of data and digital technologies to place trials in the right location, to recruit patients from the full diversity of the UK population, and to obtain follow-up data efficiently – all in ways that protect and promote the interests of patients and the public.

4.7. Decentralised trials

We want to make sure that research is available and accessible so that these are not barriers to people choosing to take part. We have published guidance, on the oversight arrangements that should be in place for an activity associated with an interventional research study, prior to that activity commencing. In describing activities that may be effectively overseen by a principle investigator (PI) at a distance, as well as activities where No PI oversight is required. The guidance helps sponsors design and manage studies around the patient. For example, by ensuring that patients are not routinely required to travel to a distant research site when this is not necessary for the study.

4.8. Electronic informed consent (eConsent)

We have published a joint statement with the Medicines and Healthcare products Regulatory Agency (MHRA), setting out the legal and ethical requirements for seeking and documenting consent using electronic methods and our joint expectations regarding the use of electronic signatures in Clinical Trials of Investigational Medicinal Products (CTIMPS). eConsent is an approach sponsors and researchers are increasingly keen to adopt and 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.

The statement, which is supported and endorsed by the UK health departments in Northern Ireland, Scotland and Wales, confirms that electronic methods may be used for seeking, confirming and documenting informed consent for participation in research.

5. Reducing research waste

The Health Research Authority has a crucial part to play in reducing research waste. Part of our work is ensuring that information about research projects is made publicly available before they start. It is crucial everyone knows what research is going on because it means researchers interested in that area can avoid duplicating the efforts of others – and avoid recruiting patients to unnecessary research. But it is also important because if we know what research is going on, we know to look out for the findings sometime in the future – and to ask demanding questions if they do not appear.

5.1. Research Transparency

Promoting transparency across the research landscape is central to the HRA’s role to facilitate safe and ethical research. Our vision is that trusted information from health and social care research studies is publicly available for the benefit of all. When research is carried out openly and transparently, everyone will be able to see what research is happening and the outcomes from finished studies. Research studies should be registered, and the results made public, so that participants are protected from unnecessary studies and research funding maximised.

Our strategy, ‘Make it public: transparency and openness in health and social care research’, sets out our vision that trusted information from health and social care research studies is publicly available for the benefit of all.

We will make transparency easy by:

• being clear about what we expect of sponsors and researchers and what they can expect of us
• supporting good practice through guidance, support and clear communication
• having a high-quality, interconnected research approvals system
• reminding researchers and sponsors when reporting is due

We will make transparency the norm by:

• working with research funding bodies and other regulators to make sure that expectations around research transparency are consistent and aligned
• rewarding and celebrating good practice and highlighting poor performance
• taking action where researchers and sponsors do not fulfil their research transparency responsibilities

We will make information public by:

• ensuring that all clinical trials taking place in the UK are registered, unless the sponsor has permission to delay this to a later stage
• publishing or sharing accessible information about individual studies and their findings
• working with partners to ensure that information for the public is easy to understand

5.1.1. Automatic registration

To avoid waste, information about research projects (other than those for educational purposes) should be made publicly available before they start (unless a deferral is agreed by or on behalf of the Research Ethics Committee).

On 1 January 2022 we started to automatically register clinical trials approved through combined review with ISRCTN registry. ISRCTN is a UK publicly accessible registry recognised by the WHO as a primary clinical trials registry. Automatic registration applies to both clinical trials of investigational medicinal products (CTIMP) and combined trials of investigational medicinal product and a medical device (IMP/device). If a trial is registered, or will be registered, with ClinicalTrials.gov the applicant can request not to be registered on the ISRCTN Registry. Automatic registration means that information about all new trial approved through combined review will be publicly available for the benefit of all. The service will be rolled out to other types of clinical trials in time.

5.1.2. Communicating results to participants

We are currently updating guidance for chief investigators, funders, and sponsors who are responsible for ensuring that study activities and findings are communicated to participants. The revised guidance sets out considerations for each stage of the study life cycle to ensure that research findings are communicated to participants appropriately and that research participants feel valued.

5.1.3. Final reports

It has always been a requirement that sponsors submit a report to Research Ethics Committees 12 months from the end of the study. In September last year, we introduced a new standard final report to make it easier to report on and measure transparency across research. In the report we ask whether researchers have fulfilled their transparency requirements. We also ask for a plain language summary of results. We publish this alongside the rest of the research summary on our website so research participants can easily find and understand the outcome of the studies.

5.2. Public involvement

Involving people with relevant lived experience in the design and development of research can improve its quality and relevance and guard against poorly designed, implemented or reported research studies.

The Health Research Authority, the National Institute for Health Research and a host of organisations across the UK have been working together to bring about changes which will drive up standards in health and social care research. Together we have signed up to a shared commitment to embedding public involvement in health and social care research.

We are committed to supporting and encouraging researchers to involve patients and the public in their work at the earliest opportunity. Public involvement in research means research that is done ‘with’ or ‘by’ the public, not 'to', 'about' or 'for' them. It means that patients or other people with relevant experience contribute to how research is designed, conducted and disseminated.

Good public involvement is worth investing in. It can lead to the development of higher quality research and make it easier to recruit and retain participants. Research teams which involve patients and the public run better studies because:

• they are more relevant to participants
• they are designed in a way which is acceptable to participants
• they have participant information which is understandable to participants
• they provide a better experience of research
• they have better communication of results to participants at the end of the study

We want researchers to make excellent patient and public involvement a normal part of their research. We will make sure researchers are aware of our Best Practice Principles and what we expect to see in an application for approval.

5.3. Information and consent documentation

We are currently running an ‘information and consent’ project, as part of the HRA’s Think Ethics campaign, which aims to develop new tools and guidance for applicants and research ethics committee members, both for designing and for evaluating the design of information and consent documentation and processes. The project will clarify how the involvement and input of public contributors will be taken into account in the ethics review of information and consent. This will benefit research participants by improving information and consent documentation and processes making research participation more ethical, effective, and inclusive whilst supporting recruitment and retention in order to improve research timelines.

5.4. Inclusion and diversity

Patients are diverse and it is important that clinical trials fully represent the population affected by the specific disease or condition that is being studied. We are working with the MHRA to propose amendments to the current UK Clinical Trials Regulations to improve the diversity of participants and are developing guidance in support of this. This will ensure the best and most reliable results from the study to the overall benefit of all patients across the UK. Meaningfully involving people in all stages of research and sharing its findings is crucial to earn people’s trust. It helps us do better research that can improve care.

As an example of the work we are doing to increase inclusion and diversity, the HRA was part of a Maternal Health Project Group, set up in the Summer 2020 by the Association of the British Pharmaceutical Industry, to address the lack of licensed medicines and treatments designed and researched for use in pregnancy and breastfeeding.

The aim was to raise awareness of the issues and make sure patients and health care providers are more informed about any decisions they may need to make. The group used the combined expertise of patients, the Medicines and Healthcare products Regulatory Agency, the Health Research Authority, clinicians, academia, and industry to make meaningful progress in four key areas:

• getting more pregnant patients involved in clinical trials
• driving investment into pharmaceutical research for medicines used in pregnancy and breastfeeding
• producing a guide on available databases at UK and EU level and promoting industry/academic use of these datasets for research
• dispelling misconceptions around maternal health and clinical trials and lowering barriers to inclusion in research

The HRA is continuing to ensure that pregnant and breastfeeding people are not excluded from participation in trials unnecessarily.

We are aware of the current consultation by WHO on ‘Public disclosure of clinical trial results’ and the ICTRP-led team’s draft recommendations for the minimum elements of study results that should be reported in trial registries. If these recommendations are adopted globally, it could enhance the standardisation and utility of the data in registries, for instance for systematic reviews and evidence synthesis. One of the proposed elements for reporting on registries is ‘characteristics of participants at baseline’ but the only specified fields are age and sex. It would be helpful to include other characteristics such as ethnicity (with appropriate standardisation of categories, recognising the difficulty of this in a global context) so that comparable data can be collected.

6. Expedited procedures for rapidly implementing clinical trials in Public Health Emergencies of International Concern (PHEIC) that meet regulatory and ethics oversight

6.1. In a public health emergency, researchers may want to urgently set up studies to test new treatments, improve diagnosis or prevent the spread of disease. The HRA can arrange to fast-track review in these exceptional circumstances and has done so in the past, for example, in relation to bird flu and Ebola. During the COVID pandemic, we were able to respond quickly, without lowering our high standards, approving studies in hours that would normally take weeks. To ensure COVID-19 research started quickly as possible, the Health Research Authority and the devolved administrations developed a fast-track process to review new studies for certain types COVID-19 research, such as vaccine studies, and amendments to existing studies, often within a few days of application. That enabled UK researchers to make the single biggest contribution to the global fight against COVID-19. More recently, the fast-track process has been used for Monkeypox research and studies affected by the war in Ukraine. When it’s most needed, review can take as little as 48 hours.

6.2. During public health emergencies it is vital that the research community and wider public are able to see information about ongoing research and its findings. During the COVID-19 pandemic we implemented a fast-track transparency process, in which information about each approved COVID-19 study was published on our research summaries website within days of approval.

6.3. We also highlighted guidance on seeking consent in COVID-19 research on how existing requirements for providing information to research participants and recording consent apply in COVID-19 research.

6.4. Ordinarily, applications are made for support from the Confidentiality Advisory Group (CAG) where confidential patient information is to be processed without consent for research and non-research activities in England and Wales. The key purpose of CAG is to protect and promote the interests of patients and the public, while at the same time facilitating appropriate use of confidential patient information for purposes beyond direct patient care. During the pandemic, a temporary arrangement (general COPI notice) was made for COVID-19 studies going through the fast-track review process, in which support from CAG was not required. However, CAG still provided advice as part of the fast-track process, as all such studies still had to apply for research ethics committee review. The notice, issued by the Secretary of State for Health and Social Care, provided a common law legal basis to process confidential patient information without consent for COVID-19 public health, surveillance and research purposes, and required NHS Trusts, Local Authorities and others to process for such purposes.

6.5. The general COPI notice expired on 30 June 2022. However, we have been working with applicants who were relying on the COPI notice to seek an alternative permanent legal basis for processing of this data such as obtaining patient consent, Regulation 3 support or applying to the Confidentiality Advisory Group (CAG) to transition to Regulation 5 (section 251) support.