NHS staff and patients engaged with research at an unprecedented scale over the pandemic. Clinical pharmacologists led national platform trials including RECOVERY and AGILE, ensuring that partnership with NHS staff was embedded in trial design and delivery.
Clinical pharmacology made contributions across all stages of the research and regulatory pathway. From the simple, large scale, phase III RECOVERY trial that was rolled out across the NHS, to the early phase AGILE trial (Professor Saye Khoo, Dr Richard Fitzgerald and Dr Lauren Walker in Liverpool) that worked through primary care and the community to run phase I and IIa trials with candidate therapeutics targeted at the early stages of the disease, aiming to address the therapeutic gap in enhancing viral clearance.
Clinical pharmacologists also advised on which candidate drugs should be prioritised for all the national COVID trial platforms (Professor Sir Munir Pirmohamed, Professor Duncan Richards, Professor Ian Hall), supporting a rational and coordinated approach to the therapeutic pipeline. Further, Chief Scientist of Genomics England, Professor Mark Caulfield, has worked with a UK wide genomic consortium (GENOMICC) to run whole genome sequencing in patients with COVID-19 to identify new therapeutic opportunities[1]. Clinical pharmacologists within industry gave advice and support to help identify medicines that could be considered as potential treatments for COVID-19 and supported vaccine development. This covered medicines that had already been approved for other indications - some of which ended up in the RECOVERY trial - and early-stage products that had a suggested mechanism of action or results that supported a possible use in COVID-19.
The RECOVERY trial, led by Professor Peter Horby and clinical pharmacologist Professor Martin Landray, demonstrated the benefits of dexamethasone and tocilizumab and definitively established that hydroxychloroquine, ritonavir, convalescent plasma and colchicine were not beneficial in hospitalised patients with severe COVID-19 disease. It was an excellent example[2] of a simple yet adaptive, trial, delivered rapidly and at scale. The platform design[3], was just as important in terms of stopping therapies which do not work. It has had a global impact on treatment guidelines, shows the value of simplified platform trials beyond COVID-19. Dexamethasone by itself has been estimated to have saved around one million lives worldwide and around 22,000 lives in the UK[4].
Observational studies embedded into routine clinical care are another opportunity to create a platform-based approach for discovery and delivery. Working with the NIHR’s Clinical Research Network (CRN), Professor Reecha Sofat used adoption onto the NIHR CRN to leverage collection of 10000 participants presenting to stroke services in two years. Data collected through the study is now being linked to electronic health care data, genomic and other blood-based data. This provides a platform for discovery for drugs that can be used to target subtypes of stroke, and when such discovery’s mature also provides a platform which can be used for trial participation including digitally enabled trials. Frontline clinical and research staff facilitated recruitment to the study, supporting its success.
On the RECOVERY trial, Professor Landray recognised the importance of making research accessible to healthcare professionals and being realistic about capacity and capability. Speaking to the BMJ, he said:
“It had to be easy for the clinician on the ground, in PPE and in a pressurised situation, and a minimal burden for the patient. Many academic and commercial trials have accumulated so much extra baggage over the years, such as long case report forms and 10-page patient consent forms.”
Professor Duncan Richards is also co-investigator on the HEAL study (which will address the excess mortality observed in people recently discharged from hospital having had COVID-19) where he is responsible for developing study design and coordinating the selection of therapies for inclusion in the study. He has also led clinical planning at Oxford University, and has reflected on the importance of partnership with frontline NHS staff and the opportunity that clinical pharmacologists have to deliver patient-centred trials that are cognisant of the reality and needs on the ground.
At the beginning of the pandemic and amid great uncertainty, Professor Reecha Sofat and colleagues established the COVID-19 Therapeutics Advice & Support Group. This is a group of experts in multiple specialties that collaborate on the appraisal, formulary work and implementation of access to medicines for COVID-19. This information has been made available to frontline clinicians across more than 20 Trusts with the aim of supporting evidence-based care and to support recruitment to trials. The group provides updates to guide use at a local level, bridging the gap to formal guidance while evidence is emerging. Clinical pharmacologists in Wales also developed a COVID Therapeutics information website for healthcare professionals. There is potential to build on this framework in partnership with NICE to improve connectivity of the therapeutic evidence base with decision-making on the ground.
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References
- Pairo-Castineira, E., Clohisey, S., Klaric, L. et al. (2021) Genetic mechanisms of critical illness in COVID-19. Nature 591, 92–98.
- Lane, H. and Fauci, A., (2020). Research in the Context of a Pandemic. New Eng J Med, DOI: 10.1056/NEJMe2024638.
- Normand, S. (2020) The RECOVERY Platform. New Eng J Med. doi: 10.1056/nejme2025674.
- NHS England (2021) COVID treatment developed in the NHS saves a million lives. (Last accessed 23 March 2021)