Correspondence
www.thelancet.com Vol 384 October 4, 2014
insufficient evidence exists to justify conclusions about oseltamivir’s effectiveness for treatment of influenza. Nguyen-Van-Tam and colleagues seem to suggest that pandemic planners should act to minimise public outcry rather than accept the best available evidence. This advice could risk scarce health-care resources stockpiling a probably ineffective drug. We declare no competing interests.
*Chris Del Mar, Peter Doshi, Rokuro Hama, Mark Jones, Tom Jefferson, Carl Heneghan, Igho Onakpoya, Jeremy Howick [email protected] Centre for Research in Evidence Based Practice, Bond University, Robina, QLD 4226, Australia (CDB); University of Maryland School of Pharmacy, MD, USA (PD); Japan Institute of Pharmacovigilance, Osaka, Japan (RH); School of Population Health, University of Queensland, QLD, Australia (MJ); Cochrane Collaboration, Rome, Italy (TD); and Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK (CH, IO, JH) 1
2
3
4
5
6
7
Nguyen-Van-Tam JS, Openshaw PJ, Nicholson KG. Antivirals for influenza: where now for clinical practice and pandemic preparedness? Lancet 2014; 384: 386–87. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Muthuri SG, Venkatesan S, Myles PR, et al; for PRIDE Consortium Investigators, Nguyen-Van-Tam JS. 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. Lancet Resp Med 2014; 2: 395–404. Roche statement. http://www.roche.com/ media/med-stat-2014-04-10.htm (accessed June 7, 2014). Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667–72. Tamiflu (oseltamivir phosphate) prescribing information. 2010. http://www.accessdata. fda.gov/drugsatfda_docs/label/2010/021087s 048s049,021246s034s035lbl.pdf (accessed June 6, 2014). Chalmers I. The development of fair tests of treatments. Lancet 2014; 383: 1713–14.
Authors’ reply We would like to thank Chris Del Mar and colleagues for their interest in our Comment.1 They assert that their Cochrane review2 was based on full clinical study reports of all manufacturer-sponsored randomised
trials. In fact, only a subset (46 of the 107 Clinical Study Reports obtained) were formally analysed. The study undertaken by Muthuri and colleagues3 was funded by Roche, but its design, conduct, interpretation, and report preparation were done independently of the funder. Exhaustive attempts were made to obtain datasets suitable for analysis from around the world. Compared with the 80 datasets received, few (n=15) were not shared because of review board or governmental restrictions (n=3), or inability to meet project timelines (n=12).3 None of the contributors of data declared industry funding for acquisition or assembly of their dataset. We do not dismiss the findings in the Cochrane review.2 The finding that no signal exists suggesting that neuraminidase inhibitors reduce serious complications2 is not unexpected in light of the fact that the clinical trials reviewed were done in community settings, were based on mostly healthy patients with mild influenza-like illness, and were not designed or powered to assess effect on severe illness. Del Mar and colleagues’ assessment of effectiveness of oseltamivir against hospital admission was based on 4394 adults and 1359 children—for pneumonia, this assessment was for 4452 patients, and for serious complications, 3675 patients. Mortality, a hallmark of pandemics and seasonal outbreaks, could not be assessed because of the absence of deaths in the oseltamivir trials. The same restrictions apply to the pooled analysis of 3564 patients in ten randomised controlled trials of oseltamivir treatment by Kaiser and colleagues,4 in which, unlike in the Cochrane review,2 these authors showed that treatment was associated with reductions in influenza-related lower respiratory complications and admission to hospital from any cause. By contrast, the observational data assembled and analysed by Muthuri and colleagues 3 used individual participant data (an approach not pursued in the Cochrane review2)
Giphotostock/Science Photo Library
Nguyen-Van-Tam and colleagues, together with the observational studies that they cite in support of their hypothesis,3 can be dismissed by our finding that neuraminidase inhibitors did not seem to reduce severe complications of influenza, and oseltamivir specifically did not seem to reduce risk of admission to hospital (admission to hospital was not reported for zanamivir), but seemed to suppress production of antibody to the virus and cause potentially serious side effects.2 Furthermore, oseltamivir reduced time to alleviation of symptoms the least for trials of patients with comorbidities such as asthma and chronic obstructive airways disease.2 The appeal to observational data in support of oseltamivir is curious because the original notion that oseltamivir was effective for treatment of influenza complications came from a meta-analysis5 of a subset of randomised trials—both published and unpublished—which was in contrast to the US Food and Drug Administration’s requirement that the drug label made no claims for effectiveness for influenza complications.6 This absence of effectiveness is supported by our Cochrane review (based on a full set of clinical study reports), which found no protective benefit of oseltamivir. Now drug manufacturers and Nguyen-Van-Tam and colleagues are claiming that randomised trial data are no longer adequate. Yet, when the results of reviews of randomised trials agreed with their views, Nguyen-Van-Tam and colleagues accepted the reviews. Now that the Cochrane review does not support their hypothesis, they appeal to contradictory real-world (observational) data.3 This inconsistency needs to be addressed. Observational data are useful to answer many questions, such as whether treatments are harmful or not. However, the fact that experimental data from randomised trials are less prone to error from bias than are observational studies is not debatable.7 The randomised trial data should therefore be trusted—
1261
Correspondence
and focused on patients admitted to hospital with severe pandemic influenza A/H1N1 2009 infection (86% laboratory confirmed).3 Many patients had risk factors for severe illness, the dataset was very large (n=29 234), and, compared with no treatment, neuraminidase inhibitor treatment was associated with a reduction in mortality risk. Although we agree with Del Mar and colleagues that randomised trials are less prone to error from bias than observational studies are,5 we do not accept that meta-analysis of existing randomised controlled trials done in community patients with “relatively benign influenza”2 and which have “problems in the design of many of the studies that were included”2 can resolve pressing questions about the role of neuraminidase inhibitors in the treatment or prevention of life-threatening influenza. We therefore reassert that the findings of the Cochrane review of Del Mar and colleagues2 do not conflict with those of the large observational study by Muthuri and colleagues,3 but that rather both studies show beneficial effects of neuraminidase inhibitors in wholly different scenarios (settings, severity, comorbidity, and background immunity). Public outcry would be justified if pandemic planners relied only on the available randomised controlled trials when making decisions about how to prevent and treat severe influenza. Between October, 2007, and September, 2010, JSN-V-T undertook ad-hoc paid consultancy and lecturing for influenza vaccine manufacturers (Sanofi Pasteur MSD, Sanofi Pasteur, GlaxoSmithKline, Baxter, Solvay, and Novartis) and manufacturers of neuraminidase inhibitors (F Hoffmann-La Roche, oseltamivir; and GlaxoSmithKline, zanamivir); he is in receipt of current or recent research funding related to influenza vaccination from GlaxoSmithKline and AstraZeneca and non-financial support (travel) from Baxter, and his group received an unrestricted educational grant for research in the area of pandemic influenza from F Hoffman La-Roche used to fund the work by Muthuri and colleagues cited in the Comment. PJMO was Vice-President of the European Scientific Working Group on Influenza until September 2014 and remains a member, and has served as a scientific adviser to GlaxoSmithKline, Sanofi, and Janssen. KGN was a founding member of the European Scientific Working Group on Influenza and resigned in 2001; within the past 5 years he received H5 vaccines from Novartis for MRC-funded research
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and H1N1 pandemic vaccines from GlaxoSmithKline and Baxter for NIHR-funded research.
*Jonathan S Nguyen-Van-Tam, Peter J M Openshaw, Karl G Nicholson [email protected] Division of Epidemiology and Public Health, University of Nottingham, Nottingham NG5 1PB, UK (JSN-V-T); National Heart and Lung Institute, Imperial College, London, UK (PJMO); and Department of Infection, Immunity and Inflammation, University of Leicester, Leicester (KGN) 1
2
3
4
5
Nguyen-Van-Tam JS, Openshaw PJ, Nicholson KG. Antivirals for influenza: where now for clinical practice and pandemic preparedness? Lancet 2014; 384: 386–87. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Muthuri SG, Venkatesan S, Myles PR, et al, for the PRIDE Consortium Investigators, Nguyen-Van-Tam JS. 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. Lancet Respir Med 2014; 2: 395–404. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667–72. Chalmers I. The development of fair tests of treatments. Lancet 2014; 383: 1713–14.
Misunderstanding “Comrades in Health” We believe that Chris Beyrer has misunderstood and mischaracterised our book, Comrades in Health: US Health Internationalists, Abroad and at Home in his review (June 7, p 1962).1 Our book is not, as he says, an “attempt to delineate a tradition in US international health efforts as part of a Marxist tradition writ large” but is, rather, a set of accounts of individuals who consider/considered themselves to be one variety or another of progressives or radicals or leftists (but not necessarily Marxist). Because of their willingness to challenge the status quo politics of development aid and technocratic solutions, those depicted in the volume and the activities in which they engaged have, over several generations, constituted a separate and different tradition from most US international health efforts. We are especially surprised that Beyrer implies
that we are apologists for Stalin, Mao, etc, when, in fact, we raise questions about those regimes and note that some of the subjects of our book may have overlooked the horrors under those regimes. It is one thing for Beyrer to disagree personally with the politics of the individuals included in this book; it is another entirely to disregard the clear and challenging contrast they present to dominant approaches to addressing health inequities between and within nations. Although we are co-editors of the book in question, all of our royalties are being donated. As such, we declare no competing interests.
*Anne-Emanuelle Birn, Theodore M Brown [email protected] University of Toronto, Toronto, Ontario M5T 3M7, Canada (A-EB); and University of Rochester, Rochester, New York, USA (TMB) 1
Beyrer C. Trust the tale. Lancet 2014; 383: 1962–63.
Ireland’s health system at a crossroads Ireland’s health system contains a complex mix of public and private financing and delivery, leading to a number of inequities within the system. However, Government proposals for a single-tier system, underpinned by universal health insurance (UHI), might not be a panacea and might lead to some people facing substantially higher costs. The Irish health system is predominately tax-financed, with substantial contributions from out-of-pocket payments (18%) and private health insurance (12%).1 About 40% of the population have medical cards (mostly means-tested but in some cases based on age or medical conditions), which entitle them to free-at-the-point-of-use primary and hospital care, prescription medications subject to a modest copayment, and a number of other, less widely used benefits. Those without medical cards must pay for these services . www.thelancet.com Vol 384 October 4, 2014
www.thelancet.com Vol 384 October 4, 2014
insufficient evidence exists to justify conclusions about oseltamivir’s effectiveness for treatment of influenza. Nguyen-Van-Tam and colleagues seem to suggest that pandemic planners should act to minimise public outcry rather than accept the best available evidence. This advice could risk scarce health-care resources stockpiling a probably ineffective drug. We declare no competing interests.
*Chris Del Mar, Peter Doshi, Rokuro Hama, Mark Jones, Tom Jefferson, Carl Heneghan, Igho Onakpoya, Jeremy Howick [email protected] Centre for Research in Evidence Based Practice, Bond University, Robina, QLD 4226, Australia (CDB); University of Maryland School of Pharmacy, MD, USA (PD); Japan Institute of Pharmacovigilance, Osaka, Japan (RH); School of Population Health, University of Queensland, QLD, Australia (MJ); Cochrane Collaboration, Rome, Italy (TD); and Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK (CH, IO, JH) 1
2
3
4
5
6
7
Nguyen-Van-Tam JS, Openshaw PJ, Nicholson KG. Antivirals for influenza: where now for clinical practice and pandemic preparedness? Lancet 2014; 384: 386–87. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Muthuri SG, Venkatesan S, Myles PR, et al; for PRIDE Consortium Investigators, Nguyen-Van-Tam JS. 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. Lancet Resp Med 2014; 2: 395–404. Roche statement. http://www.roche.com/ media/med-stat-2014-04-10.htm (accessed June 7, 2014). Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667–72. Tamiflu (oseltamivir phosphate) prescribing information. 2010. http://www.accessdata. fda.gov/drugsatfda_docs/label/2010/021087s 048s049,021246s034s035lbl.pdf (accessed June 6, 2014). Chalmers I. The development of fair tests of treatments. Lancet 2014; 383: 1713–14.
Authors’ reply We would like to thank Chris Del Mar and colleagues for their interest in our Comment.1 They assert that their Cochrane review2 was based on full clinical study reports of all manufacturer-sponsored randomised
trials. In fact, only a subset (46 of the 107 Clinical Study Reports obtained) were formally analysed. The study undertaken by Muthuri and colleagues3 was funded by Roche, but its design, conduct, interpretation, and report preparation were done independently of the funder. Exhaustive attempts were made to obtain datasets suitable for analysis from around the world. Compared with the 80 datasets received, few (n=15) were not shared because of review board or governmental restrictions (n=3), or inability to meet project timelines (n=12).3 None of the contributors of data declared industry funding for acquisition or assembly of their dataset. We do not dismiss the findings in the Cochrane review.2 The finding that no signal exists suggesting that neuraminidase inhibitors reduce serious complications2 is not unexpected in light of the fact that the clinical trials reviewed were done in community settings, were based on mostly healthy patients with mild influenza-like illness, and were not designed or powered to assess effect on severe illness. Del Mar and colleagues’ assessment of effectiveness of oseltamivir against hospital admission was based on 4394 adults and 1359 children—for pneumonia, this assessment was for 4452 patients, and for serious complications, 3675 patients. Mortality, a hallmark of pandemics and seasonal outbreaks, could not be assessed because of the absence of deaths in the oseltamivir trials. The same restrictions apply to the pooled analysis of 3564 patients in ten randomised controlled trials of oseltamivir treatment by Kaiser and colleagues,4 in which, unlike in the Cochrane review,2 these authors showed that treatment was associated with reductions in influenza-related lower respiratory complications and admission to hospital from any cause. By contrast, the observational data assembled and analysed by Muthuri and colleagues 3 used individual participant data (an approach not pursued in the Cochrane review2)
Giphotostock/Science Photo Library
Nguyen-Van-Tam and colleagues, together with the observational studies that they cite in support of their hypothesis,3 can be dismissed by our finding that neuraminidase inhibitors did not seem to reduce severe complications of influenza, and oseltamivir specifically did not seem to reduce risk of admission to hospital (admission to hospital was not reported for zanamivir), but seemed to suppress production of antibody to the virus and cause potentially serious side effects.2 Furthermore, oseltamivir reduced time to alleviation of symptoms the least for trials of patients with comorbidities such as asthma and chronic obstructive airways disease.2 The appeal to observational data in support of oseltamivir is curious because the original notion that oseltamivir was effective for treatment of influenza complications came from a meta-analysis5 of a subset of randomised trials—both published and unpublished—which was in contrast to the US Food and Drug Administration’s requirement that the drug label made no claims for effectiveness for influenza complications.6 This absence of effectiveness is supported by our Cochrane review (based on a full set of clinical study reports), which found no protective benefit of oseltamivir. Now drug manufacturers and Nguyen-Van-Tam and colleagues are claiming that randomised trial data are no longer adequate. Yet, when the results of reviews of randomised trials agreed with their views, Nguyen-Van-Tam and colleagues accepted the reviews. Now that the Cochrane review does not support their hypothesis, they appeal to contradictory real-world (observational) data.3 This inconsistency needs to be addressed. Observational data are useful to answer many questions, such as whether treatments are harmful or not. However, the fact that experimental data from randomised trials are less prone to error from bias than are observational studies is not debatable.7 The randomised trial data should therefore be trusted—
1261
Correspondence
and focused on patients admitted to hospital with severe pandemic influenza A/H1N1 2009 infection (86% laboratory confirmed).3 Many patients had risk factors for severe illness, the dataset was very large (n=29 234), and, compared with no treatment, neuraminidase inhibitor treatment was associated with a reduction in mortality risk. Although we agree with Del Mar and colleagues that randomised trials are less prone to error from bias than observational studies are,5 we do not accept that meta-analysis of existing randomised controlled trials done in community patients with “relatively benign influenza”2 and which have “problems in the design of many of the studies that were included”2 can resolve pressing questions about the role of neuraminidase inhibitors in the treatment or prevention of life-threatening influenza. We therefore reassert that the findings of the Cochrane review of Del Mar and colleagues2 do not conflict with those of the large observational study by Muthuri and colleagues,3 but that rather both studies show beneficial effects of neuraminidase inhibitors in wholly different scenarios (settings, severity, comorbidity, and background immunity). Public outcry would be justified if pandemic planners relied only on the available randomised controlled trials when making decisions about how to prevent and treat severe influenza. Between October, 2007, and September, 2010, JSN-V-T undertook ad-hoc paid consultancy and lecturing for influenza vaccine manufacturers (Sanofi Pasteur MSD, Sanofi Pasteur, GlaxoSmithKline, Baxter, Solvay, and Novartis) and manufacturers of neuraminidase inhibitors (F Hoffmann-La Roche, oseltamivir; and GlaxoSmithKline, zanamivir); he is in receipt of current or recent research funding related to influenza vaccination from GlaxoSmithKline and AstraZeneca and non-financial support (travel) from Baxter, and his group received an unrestricted educational grant for research in the area of pandemic influenza from F Hoffman La-Roche used to fund the work by Muthuri and colleagues cited in the Comment. PJMO was Vice-President of the European Scientific Working Group on Influenza until September 2014 and remains a member, and has served as a scientific adviser to GlaxoSmithKline, Sanofi, and Janssen. KGN was a founding member of the European Scientific Working Group on Influenza and resigned in 2001; within the past 5 years he received H5 vaccines from Novartis for MRC-funded research
1262
and H1N1 pandemic vaccines from GlaxoSmithKline and Baxter for NIHR-funded research.
*Jonathan S Nguyen-Van-Tam, Peter J M Openshaw, Karl G Nicholson [email protected] Division of Epidemiology and Public Health, University of Nottingham, Nottingham NG5 1PB, UK (JSN-V-T); National Heart and Lung Institute, Imperial College, London, UK (PJMO); and Department of Infection, Immunity and Inflammation, University of Leicester, Leicester (KGN) 1
2
3
4
5
Nguyen-Van-Tam JS, Openshaw PJ, Nicholson KG. Antivirals for influenza: where now for clinical practice and pandemic preparedness? Lancet 2014; 384: 386–87. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Muthuri SG, Venkatesan S, Myles PR, et al, for the PRIDE Consortium Investigators, Nguyen-Van-Tam JS. 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. Lancet Respir Med 2014; 2: 395–404. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667–72. Chalmers I. The development of fair tests of treatments. Lancet 2014; 383: 1713–14.
Misunderstanding “Comrades in Health” We believe that Chris Beyrer has misunderstood and mischaracterised our book, Comrades in Health: US Health Internationalists, Abroad and at Home in his review (June 7, p 1962).1 Our book is not, as he says, an “attempt to delineate a tradition in US international health efforts as part of a Marxist tradition writ large” but is, rather, a set of accounts of individuals who consider/considered themselves to be one variety or another of progressives or radicals or leftists (but not necessarily Marxist). Because of their willingness to challenge the status quo politics of development aid and technocratic solutions, those depicted in the volume and the activities in which they engaged have, over several generations, constituted a separate and different tradition from most US international health efforts. We are especially surprised that Beyrer implies
that we are apologists for Stalin, Mao, etc, when, in fact, we raise questions about those regimes and note that some of the subjects of our book may have overlooked the horrors under those regimes. It is one thing for Beyrer to disagree personally with the politics of the individuals included in this book; it is another entirely to disregard the clear and challenging contrast they present to dominant approaches to addressing health inequities between and within nations. Although we are co-editors of the book in question, all of our royalties are being donated. As such, we declare no competing interests.
*Anne-Emanuelle Birn, Theodore M Brown [email protected] University of Toronto, Toronto, Ontario M5T 3M7, Canada (A-EB); and University of Rochester, Rochester, New York, USA (TMB) 1
Beyrer C. Trust the tale. Lancet 2014; 383: 1962–63.
Ireland’s health system at a crossroads Ireland’s health system contains a complex mix of public and private financing and delivery, leading to a number of inequities within the system. However, Government proposals for a single-tier system, underpinned by universal health insurance (UHI), might not be a panacea and might lead to some people facing substantially higher costs. The Irish health system is predominately tax-financed, with substantial contributions from out-of-pocket payments (18%) and private health insurance (12%).1 About 40% of the population have medical cards (mostly means-tested but in some cases based on age or medical conditions), which entitle them to free-at-the-point-of-use primary and hospital care, prescription medications subject to a modest copayment, and a number of other, less widely used benefits. Those without medical cards must pay for these services . www.thelancet.com Vol 384 October 4, 2014
