Clinical Research Restart 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 patients, industry and NHS staff, as a useful aid to sites and sponsors across the UK looking to restart non-COVID research studies and trials.

Research, development and innovation at BHP

An introduction from BHP Director Professor David Adams, and Managing Director Dr 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.

We have worked with our partner organisations and the ABPI to develop this resource which will help to negotiate the challenges – and harness the opportunities – of restarting clinical research at pace. In addition, it makes recommendations on how to design the clinical trial protocol of the future, with resilience, viability and readiness built in from the outset.

UHB’s approach to tackling the pandemic

^PLACEHOLDER VIDEO^

The Clinical Research Restart Resource

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

You may also be interested in finding out about the ABPI-BHP Memorandum of Understanding and the NIHR Framework for Restart

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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 from contact within the health care setting; second, the health professionals on the research team were mostly redeployed to tackling COVID on the front-line; and third, other members of the research team were mostly seconded to research trials tackling COVID, 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 yet the UK lacks a clear strategy around regulatory science in healthcare. 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 around issues such as the Government’s Ventilator Challenge, 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 competiveness 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 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 three 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.

Finally, engaging with patients and members of the public remains critical to high quality research and clinical trials. Throughout the pandemic, PIONEER has worked with its Data Trust Committee – made up of 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.

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