Multisystem failure: the story of anti-influenza drugsBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2263 (Published 10 April 2014) Cite this as: BMJ 2014;348:g2263
All rapid responses
Medical experiments on humans (clinical trials) are carried out in the hope of improving health and furthering science. By their very nature they entail uncertainty about potential harms and benefits of a treatment or a procedure. This is why following WWII, prior ethics review by an independent committee has gradually been introduced as a key condition.
No benefit can be derived from trials which are either invisible or reported partially or selectively.
To avoid this risk, a growing number of organisations have made efforts to allow access to clinical trial results in a detail hitherto unknown.
Despite the growing international effort and a notable legislative effort in the EU, the US lags behind.
Study results posted on clinicaltrials.gov are, by definition, incomplete and unverified. Even so, eight years after the introduction of federal law FDAAA 2007 a very small number of results of registered trials have been made available and updated.
No detailed regulatory documents are available from the FDA. Physicians and patients require access to clinical study reports and anonymized individual patient data from trials of approved drugs and biologics.
US law and regulations globally affect organizational and professional behaviors with huge impact on health worldwide. The international composition of this letter's signatories reflect this reality.
We call for a statement by all US presidential candidates on whether they support access to clinical trial data held by federal agencies, irrespective of topic, sponsor, country in which the trial was run or results.
We ask that they state what measures they would put forward, if elected, to address the scandal of invisible and distorted clinical trials.
John Abramson MD MSc
Lecturer Dept. of Health Care Policy
Harvard Medical School
Boston, MA, USA
Marcia Angell MD
Department of Global Health and Social Medicine
Harvard Medical School
Boston, MA, USA
Shannon Brownlee, MSc
Senior Vice President
Vikas Saini, M.D.
President, Lown Institute
Hazel Thornton Hon. DSc (Leicester)
Independent Citizen Advocate for Quality in Research and Healthcare
Thomas Faunce PhD
Professor, jointly in ANU College of Law and College of Medicine, Biology and the Environment
Australian National University
Canberra. ACT 0200 Australia
Trisha Greenhalgh MD
Professor of Primary Care Health Sciences
University of Oxford
Oxford, OX2 6GG
Susan Bewley MD
Professor of Complex Obstetrics
Kings College London
Meryl Nass MD
Alliance for Human Research Protection
John H Noble Jr, PhD
State University of New York at Buffalo
David Misselbrook FRCGP
Senior Lecturer in Family Medicine
Kingdom of Bahrain
Miran Epstein MD PhD
Reader in Medical Ethics
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
London, United Kingdom
Trudo Lemmens DCL
Faculties of Law and Public health
University of Toronto
Carl Elliott MD PhD
Center for Bioethics, University of Minnesota USA
Lynette Reid, PhD
Department of Bioethics
Faculty of Medicine, Dalhousie University
Halifax NS B3H 4R2 Canada
James Brophy MD PhD
Professor of Medicine
Udo Schuklenk, PhD
Ontario Research Chair in Bioethics
Joint Editor in Chief of Bioethics
Queen's University, Kingston,
Matthew Herder, JSM
Associate Professor, Faculties of Medicine and Law
Dalhousie University, NS, Canada
John M. Nardo MD
Emory University Psychoanalytic Institute
The BMJ, USA
Julian Savulescu PhD
Oxford Uehiro Centre for Practical Ethics
Peter C. Gøtzsche MD
Nordic Cochrane Centre
Joel Lexchin MD
School of Health Policy and Management
Canada M3J 1P3
Sergio Sismondo PhD
Department of Philosophy
Kingston, Canada K7L 3N6
Jon F. Merz
Department of Medical Ethics & Health Policy
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA USA
Françoise Baylis, PhD, FRSC, FCAHS
Professor and Canada Research Chair in Bioethics and Philosophy
Faculty of Medicine, Dalhousie University, Canada
Barbara Mintzes, PhD
Faculty of Pharmacy, University of Sydney
Janice E. Graham, PhD
Faculty of Medicine
Dalhousie University, CANADA B3H 4R2
Adriane Fugh-Berman MD
Department of Pharmacology and Physiology
Georgetown University Medical Center
Washington DC USA
Wendy Rogers PhD
Macquarie University, Sydney, Australia
Amar Jesani, MBBS
Indian Journal of Medical Ethics
Peter R Mansfield OAM BMBS
Healthy Skepticism Inc
Hallett Cove, Australia
Alain Braillon M.D., Ph.D.
Alcohol Treatment Unit
80054 Amiens CEDEX 1. France
Richard Ashcroft PhD
School of Law
Queen Mary University of London
David H Newman, MD, FACEP
Professor of Emergency Medicine
The Icahn School of Medicine, Mt Sinai
New York, NY 10029-6574 USA
Alliance for Human Research Protection USA
Centre for Professional and Applied Ethics
University of Manitoba
Lex M. Bouter, PhD
Professor of Methodology and Integrity
VU University Medical Center Amsterdam
Department of Epidemiology & Biostatistics
Lisa Cosgrove, PhD
Professor, Department of Counseling Psychology
University of Massachusetts-Boston USA
Nancy F. Olivieri, MD
Professor, Pediatrics, Medicine and Public Health Sciences,
University of Toronto, Canada
Dale E. Hammerschmidt, MD
Professor of Medicine (emeritus)
University of Minnesota USA
Edwin Gale MD,
Emeritus Professor of Diabetic Medicine
University of Bristol, UK
Fiona Godlee FRCP
London WC1H 9JR
John Hoey MD, FRCP, FACP
Former Editor, Canadian Medical Association Journal.
Alastair V. Campbell, ThD, CorrFRSE
Professor in Medical Ethics and Director, Centre for Biomedical Ethics
National University of Singapore
Marc A. Rodwin JD PhD
Professor of Law
Suffolk University Law School
Boston, MA 02108 USA
Jay Siwek, MD
Professor of Family Medicine
Georgetown University Medical Center
Washington, DC 20007 USA
Professor Emeritus of Applied Ethics
W. Maurice Young Centre for Applied Ethics
School of Population and Public Health
University of British Columbia
Virginia Barbour MD
Marc-André Gagnon, PhD
School of Public Policy and Administration
Peter Doshi PhD
Department of Pharmaceutical Health Services Research
University of Maryland School of Pharmacy
Baltimore, MD 21201, USA
Giovanni A. Fava
Editor, Psychotherapy and Psychosomatics
University at Buffalo USA
Mark Jones PhD
School of Public Health
University of Queensland
Brisbane, Queensland 4006
Associazione Alessandro Liberati
Il Pensiero Scientifico Editore
David Tovey, FRCGP
Cochrane Editorial Unit, London, UK
Juan Erviti Lopez
Unit of Drug Assessment, Advice and Research
Navarre Regional Health Service
31002 Pamplona, Spain
Florence Bourgeois MD, MPH
Pediatric Emergency Medicine
Boston Children's Hospital
Harvard Medical School
Boston, MA, USA
Tom Jefferson MD
Centre for Evidence Based Medicine
Competing interests: John Abramson is an expert in litigation involving the pharmaceutical and device industries. Tom Jefferson receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as a consultant for Roche, in 2001-2 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral, which did not get approval from the Food and Drug Administration). TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche). In 2014-15 TJ was a member of two advisory boards for Boerhinger and is in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ has a potential financial conflict of interest in the investigation of the drug oseltamivir. TJ is acting as an expert witness in a legal case involving the drug oseltamivir (Roche). TJ is a member of an Independent Data Monitoring Committee for a Sanofi Pasteur clinical trial. Peter Doshi (PD) and Tom Jefferson (TJ) were co-recipients of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001). They are also co-recipients of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. In addition: PD received €1500 from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. PD gratefully acknowledges the American Association of Colleges of Pharmacy for its funding support ($10,000) for a study to analyze written medical information regarding the possible harms of statins. PD is also an associate editor at The BMJ. Matthew Herder is a member of the Health Policy Translation research group of the Canadian Center for Vaccinology (CCfV), which has carried out a number of clinical trials sponsored by vaccine manufacturers. MH has not been involved, in any way, with the conduct of these trials, nor received any funds from CCfV to carry out research. He has no other personal, organization, or relational conflicts of interest to disclose. Jon F Merz has received payment in the last 36 months for: 1) consultation with Novartis on issues of clinical trial design; 2) continuing membership on a pharmacogenomics ethics advisory board for Merck; and 3) being an expert witness in two personal injury lawsuits arising from research participation. Alain Braillon is a member of Healthy Skepticism, a non-profit organisation aiming to improve health by reducing harm from misleading health information (www.healthyskepticism.org/ ), and of HealthWatch-UK, a charity (#1003392) that has been promoting evidence-based science and integrity in healthcare since 1991 (www.healthwatch-uk.org/). Barbara Mintzes has acted as an expert witness in two Canadian class action suits, on post-menopausal hormone therapy and breast cancer risks, and testosterone and cardiac risks. Edwin Gale has been an expert witness in litigation involving the pharmaceutical industry. Sergio Sismondo receives royalties on sales of his books published by Wiley Blackwell. Lisa Cosgrove is the principle investigator for an RO3 grant funded by AHRQ (Grant No. R03HS022940-01A1). She has no financial conflicts of interest to report. Luca De Fiore is the president of the Associazione Alessandro Liberati - Network Italiano Cochrane, a non profit group of researchers, clinicians, and patients involved in independent clinical research and research synthesis. LDF is also the Chief Executive Officer of Il Pensiero Scientifico Editore, an independent Italian publishing company. Virginia Barbour has no competing iterests to declare. She is Chair of COPE and is employed by the Australasian Open Access Support Group, but she is not signing on behalf of either of these groups but in a personal capacity. Fiona Godlee is editor in chief of The BMJ; The BMJ is a founder member of Alltrials and is also running its own campaign for access to clinical trial data (bmj.com/open-data). Meryl Nass receives no money from government or from pharmaceutical companies and does no clinical trial work. In 2015 she practised as medicien part-time for pay and practised as a volunteer in a free clinic. Marc A Rodwin is an expert witness in qui tam litigation providing opinion on duty to disclose information and on off label drug use. None declared: Arthur Schafer, John H Noble Jr, David H Newman, John Hoey, Françoise Baylis, John M Nardo, Michael McDonald, James Brophy, Joel Lexchin, Lex M Bouter, Shannon Brownlee, Wendy Rogers, Alastair V Campbell, Juan Erviti Lopez, Mark Jones, David Misselbrook, Peter C Gøtzsche, Hazel Thornton, Amar Jesani, Peter R Mansfield, Giovanni A Fava, Janice E Graham, Jay Siwek, Miran Epstein, Vera Sharav, Trudo Lemmens, Florence Bourgeois, Lynette Reid, Susan Bewley, Carl Elliott, Jeanne Lenzer, Marcia Angell, Richard Ashcroft, Dale E Hammerschmidt, Julian Savulescu, Udo Schuklenk, Vikas Saini
Dunning questions the relevance of our systematic review, suggesting that any research data – no matter its quality -- that tests the effect of neuraminidase inhibitors on non-pandemic influenza answers the wrong question. As all randomized trial evidence is on non-pandemic influenza, he argues we must look elsewhere and highlights non-randomized observational studies which conclude the drugs provide great benefit, contrary to the conclusions which can be drawn from randomized trials.
This line of argument has been made elsewhere (1, 2), and there are several problems with it.
First, Dunning's description of the 2009 H1N1 influenza as "severe influenza, or in illness caused by pH1N1" assumes that so-called pandemic H1N1 influenza is by definition severe and non-pandemic influenza is not. Certainly seasons classed as "pandemic" get more media attention than non-pandemics, and certainly the 1918 influenza was severe, but all other so-called pandemics (1957, 1968, and 2009) had mortality comparable with non-pandemic influenza (3, 4) The randomized trial evidence does answer important questions.
Second, we are unconvinced we were wrong to exclude observational studies. We published our methodology in 2010, stating that we would focus on randomized trials. Since 2010 no experts or peer-reviewers questioned this approach.
Third, funding matters. And Dunning omits mentioning that the “systematic review” he cites as demonstrating “significant reductions in mortality in adults” was funded by Roche, oseltamivir’s manufacturer. Nor does Dunning hypothesize how a drug which confers modest benefit on what Dunning considers mild seasonal influenza could produce such stunning benefits against severe influenza. If anything, the reverse would be true.
Fourth, context. In 2003, Roche authored a paper claiming that the randomized trial data demonstrated oseltamivir reduces complications and hospitalizations. Authorities trusted Roche’s word and did not vet these data themselves. Had they done so, as we did in our review, they may have realized that the data did not support Roche’s conclusions. Knowing this, authorities might have even supported properly assessing oseltamivir in a randomized trial during the so-called pandemic of 2009. Clinical trials are ethical and the only way to answer the question Dunning says is important, unless you are seeking to defend a decision already made.
3. Doshi P, AM Trends in Recorded Influenza Mortality: United States, 1900–2004. Am J Public Health. 2008 May; 98(5): 939–945. doi: 10.2105/AJPH.2007.119933
4. Doshi P. The 2009 influenza pandemic. The Lancet Infectious Diseases - 1 March 2013 ( Vol. 13, Issue 3, Page 193 )
Competing interests: Our competing interests are the same as declared in the article (http://dx.doi.org/10.1136/bmj.g2263)
As an infectious diseases clinician and influenza researcher, I have been involved in the management of over 150 patients with severe flu since pandemic H1N1 influenza (pH1N1) emerged in 2009. Many of these patients required intensive care and some died. My personal experience of pH1N1 is not atypical: during the UK’s first post-pandemic winter (2010/11) there were 8,797 influenza hospitalisations in England alone. At the peak of the outbreak, 851 critical care beds (~20% of UK capacity) were occupied by patients with flu - mostly younger adults and children infected with pH1N1. Despite the great number of hospitalisations and deaths from influenza, antivirals were prescribed infrequently prior to admission (<3%) in contrast to generous prescription of antibacterial drugs (25% in our series). Severe pH1N1 infections continued to occur in 2013/14 and are expected to continue globally in the post-pandemic period.
The latest Cochrane review of neuraminidase inhibitors for influenza was an impressive undertaking but unfortunately addressed the wrong question. It is unable to provide the answers we need. Consistent with their previous findings the authors found that, in a randomised controlled trial (RCT) setting, oseltamivir and zanamivir modestly reduced the duration of symptoms in previously healthy individuals with uncomplicated illness caused by non-pandemic, seasonal influenza viruses. Importantly, their findings do not address antiviral effectiveness in severe influenza, or in illness caused by pH1N1, or in patients with risk factors for severe illness. Therefore, these new findings cannot guide decisions about future antiviral stockpiling or the treatment of severe flu.
Those responsible for pandemic planning and response had to rely on seasonal flu RCT data to make decisions on stockpiling and licensing. We now have abundant fresh evidence from the 2009/10 pandemic, including a recent systematic review of 78 observational studies (containing data from >29,000 patients hospitalised during the 2009-10 pandemic). After careful adjustments for confounding effects, it was shown that antiviral therapy was associated with significant reductions in mortality in adults, most notably a 50% reduction with early treatment.
The clear discrepancy between the Cochrane group’s conclusions and the extensive, global experience of antivirals suggests that something is amiss. Observational studies have limitations, but so do RCTs and systematic reviews. Observational studies are vulnerable to bias, but stringent systematic reviews of RCTs can be misleading if the findings are not interpreted in an appropriate context. Rather than focussing on RCT data alone, we need to be pragmatic when considering how to treat flu now and in the future, and when planning how to mitigate future, unpredictable pandemics. We will serve patients best by looking at - and scrutinising - all available data, while understanding and accepting the limitations of different methodologies.
If we ignore the full range of evidence we will be misled in our management. By only accepting the narrowest of definitions of acceptable evidence, we would deny patients effective treatments and endanger public health. I encourage the Cochrane Collaboration to engage with those who are developing clinical trial protocols ahead of future outbreaks and urge them to help identify sources of independent funding. Such forward planning may prevent further confusion arising for doctors and patients, but we also require balanced communication of evidence. Clinical trial data must be transparent and open, but this issue should not be conflated with the need for deployment of safe and effective antiviral drugs.
 Surveillance of influenza and other respiratory viruses in the UK: 2010-11 report, http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1296687414154 (2010).
 Dunning, J., et al. Use of antivirals and antibiotics in pandemic influenza: findings from the UK MOSAIC study. Presented at ISIRV Options for the Control of Influenza, Cape Town, South Africa. 5-10 Sept 2013.
 PHE Weekly National Influenza Report: 10 April 2014 - week 15 report (up to week 14 data), http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317141076205 (2014).
 Jefferson, T. et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 4, CD008965, doi:10.1002/14651858.CD008965.pub4 (2014).
 Jefferson, T., Jones, M., Doshi, P. & Del Mar, C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 339, b5106 (2009).
 Jefferson, T. & Doshi, P. Multisystem failure: the story of anti-influenza drugs. BMJ 348, g2263, doi:10.1136/bmj.g2263 (2014).
 Muthuri, S. G. et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data (early online publication). The Lancet Respiratory Medicine, doi:http://dx.doi.org/10.1016/S2213-2600(14)70041-4 (2014).
Competing interests: When giving talks on influenza, JD has received travel and accommodation expenses and/or registration fee waivers from the following conference/meeting organisers: European Society of Clinical Microbiology and Infectious Diseases; British HIV Association; British Thoracic Society; Public Health England; Royal Society of Medicine; International Severe Acute Respiratory and emerging Infection Consortium. JD received travel and accommodation expenses from Health Protection Agency for a pandemic secondment and from World Health Organization when serving as a technical consultant on influenza. JD has contributed to the development of local and national guidelines for the clinical management of influenza. JD is an investigator in the MOSAIC influenza study, funded by the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK.