Prepare to conduct flu trials in hospitals now, urge experts

When the next influenza pandemic hits our shores, UK hospitals must be prepared to conduct trials into the effectiveness of available antiviral drugs, according to the conclusions of a leading panel ofexperts.

Today, the Academy of Medical Sciences and the Wellcome Trust publish a report into the use of antiviral drugs called neuraminidase inhibitors (NAIs) – specifically oseltamivir (trade name: Tamiflu) and zanamivir (trade name: Relenza). The report draws on recent reviews of the evidence for the treatment and prevention of influenza using these drugs, considers possible future treatments and defines research priorities.

An influenza pandemic tops the UK’s risk register, but although there has been much research into how to prevent and treat flu during seasonal outbreaks, there is very limited evidence from flu epidemics, which are significantly different due to the increased severity of symptoms and numbers of people infected. In particular, the failure to conduct trials in the 2009 H1N1 pandemic has contributed to the current weaknesses in the evidence base.

This lack of evidence has led to recent controversies about the efficacy and effectiveness of NAIs, particularly whether or not the UK government is justified in stockpiling these drugs.

The authors of today’s report conclude that antivirals can lead to a reduction in duration of symptoms by between 14 and 17 hours for seasonal flu. However, they do not support the routine use of antivirals in patients with seasonal flu as, unless the flu strain is particularly severe or the individual is very ill, the benefits are unlikely to outweigh the risks of side-effects.

The steering group also concluded that antivirals did significantly reduce deaths in hospitalised patients, particularly if they started treatment within 48 hours of first onset of symptoms. This could be critical in a flu epidemic situation, and the report supports the use of antivirals to treat patients who require hospitalisation.

The group stresses that if future outbreaks of flu are more virulent or show greater incidence of complications and death than during the period when the current evidence was collected (i.e. mainly during seasonal flu outbreaks) then the treatment of larger numbers of the population may be justified. In other words, the more severe the epidemic or pandemic, the greater the likelihood the population will benefit from the use of NAIs.

Importantly, the steering group recommend that plans are put in place to make sure that we can learn from any future outbreak. Conducting randomised control trials of NAIs use in hospitalised patients and in high-risk groups is a high priority. It is essential that steps are taken now to put in place pre-agreed protocols and research infrastructure so that trials can begin as soon as a pandemic begins.

The report doesn’t make any recommendation on whether the government should or shouldn’t stockpile antivirals. It presents the state of the scientific evidence which should be used alongside economic, political and ethical factors when making any decisions.

Professor Sir Patrick SissonsFMedSci, Chair of the report's steering group said: “Given the huge impact an influenza pandemic could have on the nation, we want to be sure we have access to the best available options for treating influenza and preventing its spread.

"After reviewing the recent major analyses of the evidence for the impact of the two most commonly used antivirals, we can conclude that the current treatments do reduce deaths from flu in seriously ill patients requiring hospitalisation. There is evidence of some benefit in patients with seasonal influenza who are not severely ill, however this benefit is modest and may not support the routine use of antivirals in this setting. There is some, but as yet limited, evidence to support the use of antivirals for prophylaxis of influenza.

"However we emphasise that decisions about the widespread use of antivirals in a new pandemic setting must take into account factors such as the virulence of the circulating strain, cost-effectiveness, distribution and the risk of resistance. Since these may be different from previous situations, it can be difficult to apply evidence collected in one outbreak to another, and very important to learn as much as possible from any new outbreak.

"We hope that our conclusions will inform the Department of Health, Public Health England and other policymakers who are deciding how to best prepare for a possible influenza pandemic."

Dr Jeremy Farrar, Director of the Wellcome Trust and member of the steering group said: "The failure to conduct research during the last influenza pandemic has contributed to the current weaknesses in the evidence base and the uncertainty facing clinicians.

"Research on the use of antivirals – in hospitalised patients and in high-risk groups in a serious epidemic or pandemic – is a priority. It could help health professionals take the best course of action, which could mean fewer hospitalisations and deaths.

"The research protocols and infrastructure need to be put in place now - in 'peace time' - so we can start collecting new evidence immediately at the start of a new epidemic or pandemic. An assessment of the ability to do this research must be included in any scenario planning exercises for future pandemics."

The report was developed by a steering group of experts after a request from the Department of Health for an evidence-based report to inform future policy decisions. The steering group was informed by a one day workshop held in February 2015 and attended by the authors of recent studies as well as a range of individuals from clinical disciplines, public health, virology, industry and research funders.

Contacts

Giorgio De Faveri

The Academy of Medical Sciences

Clare Ryan

Senior Media Officer

Notes for editors

About The Academy of Medical Sciences

The Academy of Medical Sciences is the independent body in the UK representing the diversity of medical science. Our mission is to promote medical science and its translation into benefits for society. The Academy’s elected Fellows are the United Kingdom’s leading medical scientists from hospitals, academia, industry and the public service. We work with them to promote excellence, influence policy to improve health and wealth, nurture the next generation of medical researchers, link academia, industry and the NHS, seize international opportunities and encourage dialogue about the medical sciences.

Members of the Steering Committee and declared interests:

Professor Sir Patrick Sissons FMedSci (Chair)

Sir Patrick was formerly Clinical Vice President of the Academy of Medical Sciences (until December 2014). From 1998 he was Professor of Medicine at the University of Cambridge, and then Regius Professor of Physic and Head of the university’s School of Clinical Medicine from 2005 until retiring in 2012. His personal research on the biology and pathogenesis of human cytomegalovirus infection is supported by a Medical Research Council programme grant, which now continues under his colleagues in the School of Clinical Medicine. He was previously a non-executive director of Cambridge University Hospitals NHS Foundation Trust, and is currently a non-executive director of Cambridgeshire and Peterborough NHS Foundation Trust and a board member of the National Medical Research Council of Singapore.

Professor Jeffrey Almond FMedSci

Professor Almond is Visiting Professor to the Medical Sciences Division at the University of Oxford. He was a member of the Council of the Medical Research Council from 2008 to 2014, and was previously Head of Discovery Research and External R&D at Sanofi Pasteur, which he joined in 1999. He was also previously Professor of Microbiology at the University of Reading. He is also currently Director of Greenbank Bio Ltd (a biotechnology consultancy), a shareholder in Sanofi, and consultant to and acting Executive Chairman of VirionHealth Ltd.

Professor Deborah Ashby OBE FMedSci

Professor Ashby is Chair in Medical Statistics and Clinical Trials and Co-Director of the Imperial Clinical Trials Unit at Imperial College London. Previously she was Chair in Medical Statistics at Barts and the London School of Medicine and Dentistry, Queen Mary University of London, and held academic appointments at the University of Liverpool. She has served as a member of the UK Commission on Human Medicines and regularly advises the European Medicines Agency. She chairs the Research Methods Programme for the National Institute for Health Research (NIHR). She has previously served on the Council of the Royal Statistical Society. She has held many grants as a co-applicant and as a department head – from NIHR, the Medical Research Council, Cancer Research UK, the British Heart Foundation and the Wellcome Trust – mainly for clinical trials, and has also received Innovative Medicines Initiative funding for methodology projects. A member of Professor Ashby’s family also works for the UK Department of Health as the lead analyst for non-elective care performance (with some other responsibilities, including planning for influenza).

Professor Chris Butler

Professor Butler is Professor of Primary Care at the University of Oxford and a general medical practitioner in South Wales. He is Clinical Director of the University of Oxford Primary Care Clinical Trials Unit. He is the Work Package Leader of the EU FP7-funded “Antivirals for influenza-like illness? An RCT of clinical and cost effectiveness in primary care” (ALIC4E) study, which is part of the Platform for European preparedness against (re-)emerging epidemics (PREPARE) consortium. He is on the MRC Efficacy and Mechanisms Evaluation Board of the Medical Research Council. He is the Chief investigator of the “Point of care testing to target antibiotics for chronic obstructive pulmonary disease exacerbations”(PACE)study which has been supported in the form of a non-restrictive educational grant of the loan of C-Reactive Protein assay machines and associated support from the international diagnostics company Alere. He has also received fees personally from Alere for presenting and participating in a workshop on point of care testing using C-Reactive protein for common infections in primary care.

Dr Jeremy Farrar OBE FMedSci

Dr Farrar has been Director of the Wellcome Trust since 2013. He was previously Director of the Oxford University Clinical Research Unit in Vietnam. He has served on World Health Organization advisory committees, and is currently on the board of directors of Genome Research Ltd and a member of the council of the Foundation for Science and Technology.

Sir John Skehel FRS FMedSci

Sir John is Emeritus Scientist at the Francis Crick Institute, Mill Hill, London, and Biological Secretary of the Royal Society. He was Director of the WHO Collaborating Centre for Reference and Research on Influenza from 1975 to 1994 and Director of the National Institute for Medical Research, Mill Hill, from 1987 to 2006.

About the Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art.