Clinical Research Restart & Recovery Resource

close up shot of scientist pipetting solution into test tubes

Covid-19 has had a significant impact on non-Covid clinical research, with many studies still paused due to the pandemic.

This Clinical Research Restart Resource has been developed by BHP and ABPI, co-produced with patient involvement leads and NHS partners, as a useful aid to sites and sponsors across the UK who are restarting non-Covid research studies and trials as part of post-pandemic recovery.

An introduction from BHP Director Professor David Adams, and Managing Director John Williams

The resilience of the UK’s research and innovation ecosystem in the face of an unpredicted health challenge has undoubtedly been enhanced by the existence of interconnected ecosystems of health research excellence like BHP.  Our people, their ability to access technologies and methodologies, high patient flows and local industrial partners with relevant capabilities were critical in shaping the local response to Covid-19, with our impact felt internationally.

As we move forward in the post-pandemic environment, and our organisations and workforces slowly recover from extreme pressure, we now need to reflect – how do we build back the diverse research activities that are key to how we address both long standing health challenges and newly emergent research questions?

Research-active hospitals are known to achieve better care outcomes for the patients they treat and, with clinical research strongly embedded across the six hospitals that make up BHP’s two NHS members, the Covid-19 pandemic drastically changed their dynamics.

At Birmingham Women’s and Children’s NHS Foundation Trust, collaborative working with the University of Birmingham resulted in pioneering research into paediatric Covid-19 treatments, the link between the virus and the rare Kawasaki-like syndrome in children, and the new disease paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS).

University Hospitals Birmingham NHS Foundation Trust dealt with greater numbers of Covid-19 patients than anywhere in the country. 13,766 patients were admitted in the year to 7 May 2021 and, although it was able to set up urgent public health Covid-19 studies in an average of just seven days, more than 90% of its existing clinical trials had to be paused.

While Covid-19 research is still vital as we cautiously emerge from restrictions – particularly around vaccine efficacy – recommencing other clinical trials and research is essential in improving the health and wealth of the country. Principal investigators and industry sponsors face a considerable challenge: prioritising the order of restart, meeting preconditions and managing capacity must be tackled alongside reassuring patients and redesigning studies to include remote or community monitoring of participants.

In partnership with the ABPI, Birmingham Health Partners has developed this resource, which we hope supports others in the national effort to restart clinical trials and recover from this pandemic, as laid out in the Government’s UK-wide vision for clinical research delivery. This Clinical Research Restart & Recovery Resource sheds a light on how our Trusts have dealt with the challenges of the pandemic, including restart – and how patient involvement, innovative regulation, use of health data and novel ways of delivering trials, must all play a key role in rebuilding and transforming the UK’s clinical research environment.

UHB’s approach to tackling the pandemic

UHB has a vast clinical research portfolio, with almost 900 studies currently open across Covid-19 and non-Covid trials. This infographic highlights the wide range of research activity that has taken place at the Trust since the pandemic began, up to 27 April 2021:

The Clinical Research Restart & Recovery Resource

Click the headings below to explore the ABPI-BHP Clinical Research Restart & Recovery Resource. 

You may also be interested in finding out about the ABPI-BHP Memorandum of Understanding and the NIHR Managed Research Recovery Process.

University Hospitals Birmingham (UHB) has developed an Assess-Arrange-Confirm process which details the steps sponsors, Principal Investigators (PIs) and delivery teams – including imaging, pharmacy and governance departments – are taking on the route to restart. 

PDF: Download the Assess-Arrange-Confirm decision tree.

Authored by Margaret O’Hara, Patient and Public Involvement and Engagement in Research Lead, UHB.

With acknowledgements to Laura Chapman, Laura Nice, Magdalena Skrybant, Laura Forty – PPIE Managers for NIHR Birmingham BRC, NIHR SRMRC & SSF-CfCWR, NIHR ARC WM, and PIONEER

      • Creating an environment for co-production

At Birmingham Health Partners, our patient and public involvement (PPI) team have spent years developing good working relationships and building trust with members of the public and clinical investigators. The team act as ‘boundary spanners’ in a fast-moving environment, facilitating complex conversations and supporting the meeting of worlds between researchers, patients and the public. This has provided us with the basis upon which to rapidly respond to the rapidly evolving research landscape during the Covid-19 pandemic.

      • Patient and public involvement in the response to Covid-19

When the pandemic hit back in March 2020, one of the first things we noticed was the steady stream of meeting cancellations. This was partly due to simply not being able to physically meet and we hadn’t yet got the hang of using virtual platforms. It was also because of a turning of attention towards the coming crisis. Discussions about upcoming research were shelved as clinical academics diverted away from their research activities towards frontline clinical service.

Very quickly though, the space which had been left vacant by research being paused was filled with new, rapidly instigated Covid-19 studies. The Health Research Authority soon noted that few of these Covid-19 studies had PPI embedded. They were concerned that it appeared as though patient involvement was regarded as an optional extra which could be dropped. There may also have been perceptions among academics that there was simply not enough time to involve patients.

At BHP we responded to the need for rapid PPI in Covid-19 research by establishing a Rapid Response PPI Group. Public involvement professionals working across NIHR and other infrastructures based at UHB and UoB work as a team, and we network with other staff facilitating PPI groups across campus. We worked closely together and were able to quickly recruit experienced and knowledgeable public contributors who were keen to contribute and willing and able to respond to the need for rapid turnaround. It is our usual practice to give our public contributors plenty of notice and to not ask them to do things at the last minute. However we all understood the nature of the crisis and our public contributors rose to the occasion.

Some investigators can feel shy about asking public contributors to do more involvement work when there is a flurry of applications all at once, but our public contributors want to be ‘bothered’ – they want to do the work. They would rather be asked and say no if they don’t have the capacity than not be asked in the first place. When the pandemic hit, our public contributors wanted to do their bit for the health service and the UK’s response to the pandemic.  The opportunity to get involved in research was a chance for patients and the public to play their part in this national effort.

After the initial response to the first wave we realised that face-to-face meetings were not going to be possible for the foreseeable future. This applied both to meetings with members of the public but also to our twice-monthly PPI drop-in sessions which offer bespoke support to investigators. This necessitated a rapid shift to virtual ways of working. While this was an easy transition for our academic and clinical colleagues, we spent a great deal of time and effort in supporting our public contributors to be able to use these new platforms.

      • Patient and public involvement in clinical research recovery

Building on our Covid-19 experiences and looking ahead to restart and recovery, it will be extremely important to retain the benefits of remote meetings while also accommodating those who prefer face-to-face, or those who do not have the means to take part in virtual platforms.

In addition, we must be ready for whatever challenges may present themselves in the future, with partnerships and ways of working established to help us respond. It takes time to establish long-term relationships between the research community and patients and the public, so research active institutions and companies need to invest their time and effort in building those relationships.

The pandemic also shone a spotlight on health inequalities, which were always there but did not necessarily receive the attention they deserved. So we will need to invest in relationship building with under-served communities to support more inclusive opportunities for all and ensure we are measuring the outcomes which matter most to patients and the public.

One of our public contributors, Tony Kelly describes how the phrase “hard to reach” groups is greatly disliked and that we should be doing more to engage with patients and the public. “If I can reach them in my voluntary capacity, so can everyone else anyone else. We need to get from behind our desks and go and engage,” he says. 

It is essential that we do not entrench existing health inequalities but rather act to reverse them and by conducting good quality, meaningful PPI, we can help ensure we deliver on this and maintain the quality and real-world relevance of the health research we do in the future.

It is probable that the pandemic has created even more barriers to participation in research. People may be reluctant to attend hospitals for what are seen as discretionary research visits as they don’t want a potential exposure to Covid-19. Many appointments have moved to virtual platforms so there are fewer patients physically attending hospital sites who could be approached. These factors make it all the more important to involve the public at every stage of research from design to dissemination. We need to understand people’s concerns and motivations and co-develop ways of doing and understanding research which work for everyone. Just as healthcare provision has had to adapt to the new reality, so the health research community may have to innovate.

      • Top tips for conducting meaningful patient and public involvement
      1. Ask patients and the public directly what they want and need from research
      2. Make sure you have identified and can explain the benefit that PPI can bring to research
      3. Invest time into building relationships with patients and the public in your local community
      4. Use existing resources and tools to help develop and embed good practice

In the UK, Covid-19 study recruitment has seen an expedited trial approval system made possible by the Government’s Urgent Public Health Research (UPHR) prioritisation process and badging process, and the Health Research Authority (HRA)’s and Medicines and Health products Regulatory Agency (MHRA)’s risk-based and pragmatic approaches to research approval, delivery and conduct.

For staff within the Research, Development and Innovation (RD&I) team at BHP founder-member University Hospitals Birmingham NHS Foundation Trust (UHB), this has led to a marked change in trials set-up and site activation practices for UPHR studies. By introducing a centralised and coordinated assessment process for site capacity and capability, we have seen rapid contract processes with the first patient first visit within 48 hours, which has rarely been witnessed before.

As in many trusts with an established research infrastructure, a crucial element to successful patient recruitment has been the formation of a combined Covid-19 research delivery team. At UHB this team consists of staff from across departments and facilities, mobilised into a central team, allowing for 24-7, seven-day recruitment across all sites. This has supported a varied portfolio of studies and trials.

Alongside this team reconfiguration, the NIHR UK Clinical Research Facility Network (UKCRFN) provides a national CRF capability which works effectively and efficiently to identify trial delivery sites.  The UKCRFN Managers signpost feasibility requests to their group enabling an expedited route to site identification. During Covid-19 this has been more evident than ever, with colleagues joining together to ensure the four UPHR platform trials were available across this national network and avoiding competing treatment arms at any one site.

Alongside this has been a crucial portfolio of staff testing studies that have been led by the RD&I team, which have shown a prevalence rate of approximately 3% for asymptomatic staff carrying Covid-19 during the first wave of the pandemic. To date, recruitment drives to various staff testing initiatives has seen unprecedented activity of over 20,000 staff tested and over 500 participants recruited and tested in one 24 hour period within the CRF. 

The Birmingham CRF is also providing the infrastructure to deliver seven Covid-19 vaccine trials, having shown the ability to recruit to time and target – with one vaccine study exceeding the recruitment target within 48 hours over a weekend.  Covid-19 research at UHB has been made possible thanks to the flexible working of the Covid-19 research team and the expertise of the experimental medicine workforce. 

UHB are extremely pleased with our response to the pandemic and it is this that has helped recruit around 90% of patient admissions to Covid-19 trials.

As much as possible, ways of working evolved during the pandemic, which included the use of a real-time clinical dashboard to aid patient recruitment, agile team-working and prioritisation – with these initiatives set to be continued as the trust moves forwards. The trust are committed to delivering as much research as possible to benefit the greatest number of patients, subject to wider and local NHS recovery and restoration plans and the usual study approvals, ethical permission and agreed costings with the collaboration and support of sponsors.

By Professor Alastair Denniston, Dr Eliot Marston and Professor Melanie CalvertBirmingham Health Partners Centre for Regulatory Science and Innovation

Covid-19 has highlighted both the complexities and opportunities in bringing new diagnostics, medicines, medical devices and vaccines to market at pace, showcasing flexibility and rapidity of collaborative responses by academia, industry, health services and, crucially, our regulatory agencies.

In parallel we must recognise the profound disruption that the pandemic caused to existing research in almost all areas outside of Covid-19. There was widespread cessation or at least pausing of many research programmes and clinical trials, and some of these have since been terminated.

Non-Covid trials were hit with three separate challenges: first in most instances it was felt inappropriate to ask study patients to attend for research visits given the possibility of contracting Covid-19 from contact within the health care setting; second, the health professionals on the research team were mostly redeployed to tackling Covid-19 on the front-line; and third, other members of the research team were mostly seconded to research trials tackling Covid-19, such as the well-known RECOVERY trial. Clinical trials vary in the extent to which they build in resilience of design, but it is fair to say that even the most cautious investigators generally do not include a pandemic in the contingency plans.

In the UK, the subsidence of the first wave in mid 2020 allowed an initial reopening of many clinical trials. Further disruption came in late 2020 with a second pandemic wave which extended through the winter, although the extent of this disruption was felt differently across the country. In 2021 the benefits of wide-scale vaccination have again tipped the scales, and clinical research programmes are getting back up to speed, but as with many other aspects of life we now have the opportunity to reflect and learn. We have the ability to rethink the way we design and regulate clinical trials to ensure that, in the event of a future emergency situation, we are able to continue research safely.

Similarly, our ability to accelerate innovation not only in cutting-edge technologies such as vaccines through to novel AI systems for screening, triage and decision support, but also in low-cost, high-volume products such as PPE, will redefine the way we approach research in the future. All of this hinges on our regulatory environment.

Flexible, targeted innovation in regulation is a key priority in a host of recent UK research strategy recommendations, from the R&D Roadmap, Life Sciences Recovery Roadmap, and ‘Regulation for the Fourth Industrial Revolution’, and our departure from the EU adds a significant, specific national need for adaptation in our regulatory environment –  carrying opportunity and risk that must be carefully managed.

Patient safety and trust are central issues. The major public concerns over the global vaccine ‘race’ have no doubt added to existing anti-vaccination beliefs and misinformation. Additionally, patients may feel reluctant to – or anxious about – returning to clinical premises to continue their participation in clinical research. The recent Cumberlege Review is a harrowing but vital reminder of the importance of making patient safety central to regulation, with amendments made to the UK’s Medicines and Medical Devices Bill before it was granted royal assent to rebalance the need for any new regulations to ensure the ‘attractiveness’ of the UK with much-needed priorities around patient safety.

To tackle these issues, the UK must take a coordinated approach to foster and prioritise advances in regulatory science and innovation and build a workforce to ensure its sustainability and continuing evolution. Making patients and the public central to these efforts – through co-design of research and regulation input – is vital to promote patient safety and trust in our healthcare system and drive uptake and use of innovative medicines and devices. This will require significant cross-sector collaboration, uniting industry, academia, NHS, funders, charities, regulators and citizens, with major investment to realise the profound healthcare, societal and economic benefits of targeted regulatory reforms, standards and flexibilities.

While this must be a national effort, the Midlands is already providing a beacon of leadership for UK regulatory science. The Midlands has around 1,000 medical technology companies operating in the region, the largest such cluster in the UK, delivering around £1.6 billion GVA annually – a sector set to be massively impacted by new regulation, with a “very real and concerning lack of readiness”.

Birmingham Health Partners hosts the Centre for Regulatory Science and Innovation and led the ‘Advancing Regulatory Science and Innovation in Healthcare’ report which provided a national call to action in 2020, supported by bodies ranging from the Government’s new Regulatory Horizons Council, ABPI and the Association of British HealthTech Industries (ABHI) to patient advocates.

Our academic and NHS leaders have recently set the first international standards for reporting of clinical trials of AI, publishing their findings and the new guidelines simultaneously in Nature Medicine, The BMJ and The Lancet Digital Health. Experts in our Medical Devices Testing and Evaluation Centre (MD-TEC) advised both Cabinet Office and industry throughout the pandemic, and are now pivoting support to PPE production and preparing companies for future uncertainty. More recently, we have worked closely with the Regulatory Horizons Council to build an evidence base around the direction of travel for medical devices regulation in the UK, and discussed opportunities for UK innovation with the Government’s Taskforce on Innovation, Growth and Regulatory Reform.

Regulatory innovation is an urgent opportunity and necessity for the UK, underpinning global market competitiveness and citizen access to timely, safe and effective healthcare innovation as well as ensuring the continuation of clinical research even in challenging times – an agenda in which the Midlands continues to play a pivotal enabling role.

Reflections from Professor Tom Clutton-Brock,  Director of the Medical Devices Testing and Evaluation Centre, on safety, performance and usability testing of novel ventilators in response to Covid-19 – The National Ventilator Challenge.

Early in 2020, reports from China and Italy highlighted the critical importance of ventilator availability to treat Covid-19 patients.

Following an audit which revealed a national shortage of much-needed ventilators, a UK consortium of industrial, technology and engineering businesses from multiple sectors were quickly mobilised to manufacture additional equipment and, in Birmingham, the NIHR Trauma MIC and MD-TEC (Medical Devices Testing & Evaluation Centre) team led the investigation of a range of novel ventilator design options to meet a high-level specification for a Rapidly Manufactured Ventilator System.

The NIHR Trauma MIC Team is located within MD-TEC, a facility housing a fully equipped simulation suite with an operating theatre, intensive care unit, ward and outpatient areas. It has state-of-the-art simulation mannequins, audio-visual equipment and live-streaming capabilities that were used by the consortium to test medical devices, generating evidence to be used as part of the regulatory approval process. 

As part of the Ventilator Challenge, the team initially contributed to the manufacturing specifications for ventilators, continuous positive airway pressure (CPAP) systems and syringe drivers. In all, 50 prototypes of 12 novel ventilators, CPAP systems and non-invasive ventilation systems were received and underwent multiple rounds of safety, performance and usability testing in MD-TEC’s Simulation Suite within 48 hours of the device being received on site.

After just 12 weeks of work, Penlon’s ES0 2 ventilator was the first machine to be approved for use in hospitals with large-scale production facilities set up – a process that would usually take years. This could only have been achieved by collaboration between multi-sector industry partners converging around MD-TEC and its clinical-academic team of human factors engineering and usability specialists.  

The Penlon Ventilator undergoing testing in MD-TEC's simulation ward
The Penlon Ventilator undergoing testing in MD-TEC’s simulation ward

 

The device is a new ventilator design, adapted from previous models and designed to provide support to critically ill patients with a range of functions including volume and pressure-controlled ventilation as well as spontaneous breathing support.

Importantly, the Ventilator Challenge Consortium is now capturing lessons learned to share them across the engineering community – and with Government – as key tools to not only ensure preparedness for the future, but to re-evaluate the way complex devices and medical technologies are trialled and implemented. This will enable the UK to develop, test, validate and implement much-needed innovations when needed at a far greater pace than previously, while still maintaining rigorous levels of safety.

Through our involvement in this Challenge and by supporting the supply of a total of 13,437 ventilators, this project has enabled the NHS to build resilient stock should ventilators need to be available in large numbers in the future. As NHS resilience is also critical to our ability to restart our research portfolio, innovations such as these support the local and national effort to recover from this pandemic. 

BHP is home to PIONEER, the Health Data Research UK (HDR UK) hubs for acute care, which is led by UoB and UHB Professor Liz Sapey. Here she reflects on the significant contributions that health data has made to the UK’s pandemic response, and the impact data will have on post-Covid research.

Since launching in October 2019, the seven HDR UK hubs have demonstrated that their uniquely collaborative, cross-sector and fast-paced method of working delivers results that make a difference to patients’ lives.

In the past year the Hubs also had to rapidly switch their focus to supporting the UK’s response to the Covid-19 pandemic, and nowhere was this more relevant than in acute care which bore the brunt of the disease. PIONEER led 12 projects across NHS, academia and industry, including designing and implementing a fully electronic screening and management system, and also developed a real-time Covid-19 dashboard which provided a fast-track screening tool for nationally-prioritised clinical trials. The dashboard has (as at April 2021) supported more than 10,000 recruitments for the NIHR Clinical Research Network.

PIONEER also mobilised an alliance with University College London, UCL Hospitals and the Alan Turing Institute to form DECOVID, which curated and housed matched Covid data from the four UHB hospitals with UCLH. These data were used to answer freely submitted questions (an ‘Open Science’ approach) with analysts and researchers across the country focusing on varying aspects of wave 1, 2 and 3 disease. Separately, PIONEER shared Birmingham Covid-19 data with other academic centres and organisations including the West Midlands Applied Research Collaborative, ONS, and the BHF Cardiovascular HIC, contributing to national research priorities.

As a result of the first year of Covid-19, PIONEER believes there are four critical ways in which health data can not only facilitate the swifter reopening of clinical trials, but also streamline and improve clinical trial design moving forwards.

      • Use real-world data to inform fast-screen feasibility studies and identify whether the relevant participant population exists in sufficient numbers

PIONEER is one of the most complete records of acute healthcare journeys available for research innovation. Our data is condition- and disease-inclusive: it focuses on the patient in their entirety without a disease or organ-based approach, so PIONEER captures a wealth of data including: reason for seeking care; medical history; physiology readings; imaging reports; severity and complications; treatment plan; and outcomes and follow-up.

Covering the large, stable and diverse Birmingham and West Midlands population initially, PIONEER currently holds approximately 21 years of longitudinal data on over 1 million patients, including 70m drug administrations, 100m blood pressure readings, and 200m blood test results.

Interrogating data on this extensive scale can help design highly specific protocols, select the most appropriate recruiting sites for trials and ensure the diversity required of clinical trials.

      • Increase use of e-capture for monitoring and self-reporting of symptoms

With patients unable or reluctant to attend clinic for consenting and follow-up appointments, it may be time to consider when in-person visits are genuinely necessary. E-consenting could be achieved using secure videoconferencing platforms and electronic forms, while the steady stream of advances in wearable technologies and remote patient monitoring could negate the need for participants to attend as many visits as they have done in the past. This is less onerous for patients and allows clinical trial data to be gathered even if clinical facilities are out of bounds or clinicians redeployed.

      • Implement remote and community interventions

Some clinic visits are of course inevitable for trial participants – for example in order to take blood or X-rays. But does a large hospital always need to be the destination? Could Principal Investigators ‘outsource’ such investigations to the patients’ own GP, community healthcare facilities and walk-in centres, home visits or even via private centres? In the short term, patients may feel more reassured visiting a ‘Covid-secure’ environment while in the longer term, patient convenience and reduced carbon footprint are just two of the benefits.

Providing there is appropriate, secure IT infrastructure in place to send results directly to the trial hub, both community and self-monitoring offer tangible benefits to clinical trial leads – both in the wake of Covid-19 and in ‘normal’ times.

      • Engage with patients and members of the public

As already outlined in this resource, the patient voice remains critical to high quality research and clinical trials. Throughout the pandemic, PIONEER has worked with its Data Trust Committee – made up of Patient and Public Involvement and Engagement (PPIE) partners – to set its data access protocols, review all data access requests, and even produce a guide to PPIE for researchers to ensure public involvement takes place throughout the full lifecycle of research. PIONEER, along with its six sister hubs, have proved that PPIE can be successfully undertaken remotely and virtually – not as an ‘add on’, but as an integral part of core business.

Covid-19 represents the only public health crisis most of the UK population will have lived through in close proximity. Not only has the pandemic touched every member of society and given them a unique viewpoint, but it has catalysed greater interest in clinical trials and research among many people who may previously have not had an interest. Evidencing strong PPIE in all clinical trials can only build public trust in research and its outputs.

For further information, please contact:

Richard Fox

Strategic Business Engagement Partner, Life Sciences – University of Birmingham

T: +44 (0)121 371 8474 //  +44 (0) 7964 908 616

Su Jones

NHS Engagement Policy Partner, ABPI

T: +44 (0)2007 747 7178

Jennifer Harris

Medicines Development Policy Manager, ABPI

T: +44 (0) 207 747 1434