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A new systematic review of clinical studies of the oral anti-influenza drug oseltamivir that included a substantial amount of clinical data that were not part of previously published assessments showed that significant questions exist about oseltamivir’s role in treating and preventing influenza and in pandemic preparedness.
"Our results show that oseltamivir reduces the proportion of participants with symptomatic influenza when used for prophylaxis and has modest symptomatic effects when used for treatment, but it also causes nausea and vomiting and increases the risk of headache and renal and psychiatric syndromes," Tom Jefferson, Ph.D., wrote in an article published online on April 9 (BMJ 2014;348:g2545 doi:10.1136/bmj.g2545).
"We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug," concluded Dr. Jefferson, an epidemiologist with the Cochrane Library and head of the Italian Health Technology Assessment program in Rome, and his coauthors. "The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling," they wrote.
A second, simultaneously-published study by the same Cochrane-based group using previously unavailable clinical-study data for zanamivir, an inhaled anti-influenza drug, found that, while zanamivir treatment safely reduced by half a day the time to improvement in adults with symptomatic influenza, it had no effect on reducing the risk of complications of influenza, particularly pneumonia, or the risk for hospitalization or death, nor did it show any efficacy for reducing asymptomatic influenza and the subsequent risk for transmission (BMJ 2014;348:g2547 doi:10.1136/bmj.g2547).
The newly available data used by the Cochrane researchers in both reviews came from the manufacturers of the two drugs, Roche in the case of oseltamivir (Tamiflu) and GlaxoSmithKline in the case of zanamivir (Relenza). "Owing to the risk of reporting bias there are legitimate reasons to doubt the stated benefits of oseltamivir and the results of previous Cochrane reviews of neuraminidase inhibitors in adults and children," wrote Dr. Jefferson and his associates in the oseltamivir report.
"To tackle these problems, we have conducted a 4-year campaign to obtain full study reports of the oseltamivir trial program" as well as a parallel campaign that yielded full study reports for zanamivir. The 4-year campaign noted in the review involved an unusual collaboration between Dr. Jefferson and his Cochrane associates and editors at BMJ to put ongoing pressure on Roche and GlaxoSmithKline to promise and then follow through on delivering the full clinical reports from the drugs’ studies, data that finally reached the Cochrane researchers in late 2013.
"For the first time, a Cochrane review [on neuraminidase inhibitors] is based on all relevant full clinical study reports of a family of drugs, integrated by regulatory comments," the authors wrote. "We are pretty confident that this is the closest you’ll get to an unbiased data set," Dr. Jefferson added in an interview.
Despite the unprecedented completeness of the data behind the two reports and the questions they raise about the two drugs, Dr. Jefferson expressed skepticism that public health policy in the United States or United Kingdom will change as a result of the publications.
"I don’t think the people who made the decision to stockpile these drugs for influenza can make an objective decision with any new evidence. [Oseltamivir] was stockpiled but the evidence of its toxicity wasn’t ‘discovered’ by us. It’s been known since the 1990s. I’m skeptical [there will be change now] because the whole system needs to be overhauled. Individual physicians are very loath to prescribe these drugs. But for public health decisions I’m not holding my breath," Dr. Jefferson said.
In reply to a request for comment on the new reports, Gregory Härtl, a spokesperson for the WHO in Geneva, made this statement: "WHO has not seen the paper so cannot comment on specifics. We welcome a new and rigorous analysis of available data and look forward to consideration of its findings after it appears. WHO is committed to an evidence-based approach to determining the best advice for patient care."
Jason McDonald, a spokesperson for the Centers for Disease Control and Prevention in Atlanta made this statement: "CDC supports efforts to make public previously unpublished data from clinical trials. CDC and its advisory committee on immunization practices review all relevant scientific literature when making policy decisions about public health. Clinical trials are just one component of the overall body of scientific evidence that CDC and ACIP [Advisory Committee on Immunization Practices] review when making clinical recommendations on antiviral drugs. Observational trials are another such component, and CDC and ACIP have reviewed a considerable and ever growing number of such studies that show the benefits of antiviral medications in not only reducing and shortening symptoms of disease but also preventing hospitalizations and deaths, including in high risk children and adults. While there are limitations and possible biases that must be considered and controlled in such studies, these studies are easier to conduct due to ethical considerations and more of them are available.
"CDC welcomes the public release of all such data for academic review and discussion. These data have not changed CDC and ACIP’s recommendations for the clinical use of antivirals in the United States. Decisions regarding the purchase of antivirals for use in the U.S. Strategic National Stockpile in the event of an emergency are not made by CDC.
"It’s important to acknowledge that the neuraminidase inhibitor class of antiviral drugs, which includes Tamiflu and zanamivir, are a second line of defense against the flu. These drugs represent an important tool in the event of a flu outbreak, when a vaccine isn’t yet available. Such drugs are often the only treatment option available for flu, and while we all support the development of new and better drugs in the future, we must make the best use of the tools we have at our disposal to promote public health."
In June 2013, a multidisciplinary and international group of researchers developed an independent statistical plan for analyzing the full oseltamivir dataset with an eye toward determining the efficacy and safety of oseltamivir for treating and preventing influenza in both individual patients and for public health. The Multidisciplinary Group for Advice on Science (MUGAS) plans to present the results of its analysis in September at a meeting of the European Scientific Working Group on Influenza, according to Dr. Richard J. Whitely, professor and director of pediatric infectious diseases at the University of Alabama in Birmingham, and one of the organizers of the MUGAS project on oseltamivir.
Dr. Jefferson receives royalties from Blackwells and Il Pensiero Scientifico Editore, Rome, and gives interviews anonymously to market research companies about phase I or II pharmaceutical products. In 2011, he was an expert witness in a litigation case related to oseltamivir phosphate and in a labor case on influenza vaccines in health care workers in Canada. He has been a consultant for Roche, GlaxoSmithKline, and Sanofi-Synthelabo, and is currently a consultant for IMS Health.
BMJ support key
Dr. Jefferson called his 4-year effort to get full clinical-testing data on oseltamivir and zanamivir from the manufacturers a "campaign," and cited key support from the staff of the U.K.-based BMJ medical journal.
"If BMJ had not become involved neither Roche nor GlaxoSmithKline would have cooperated. BMJ pledged their support when we asked for the full clinical reports" in 2009, recalled Dr. Jefferson, who first raised the issue of getting wider data access and also led the Cochrane analysis on the new data.
The story began in 2009, during the H1N1 pandemic, which led to the Cochrane group’s receiving funding to perform an update to a neuraminidase-inhibitor review they had done in 2006. In the intervening years, information emerged suggesting a large cache of unpublished data had never been seen during the 2006 review, which focused on published materials.
"In 2011, we decided not to accept anything that had been published because it was biased," Dr. Jefferson said in an interview.
BMJ editors compiled details and links on this web page to the thrusts and parries between themselves and Cochrane staffers and the two companies involved, Roche and GlaxoSmithKline, during the several years it took to receive and evaluate the full data: www.bmj.com/tamiflu.
In an editorial accompanying the two reports from Cochrane on oseltamivir and zanamivir, Dr. Fiona Godlee, editor-in-chief at BMJ, Dr. Elizabeth Loder, another BMJ editor, and Dr. David Tovey, editor-in-chief of the Cochrane Library, called the Cochrane reviewers and their associates who authored the two papers "pioneers" for "navigating the uncharted territory" of the data analyses they performed using huge numbers of clinical study reports (BMJ 201;348:g2630 [doi: 10.1136/bmj.g2630]).
Dr. Loder, Dr. Tovey, and Dr. Godlee also said in their editorial that they saw the effort to get more data on the neuraminidase inhibitors as part of a larger effort to remake the way that drugs are assessed and reviewed.
The process required to obtain and analyze the neuraminidase inhibitor data showed "with greater clarity than ever that the current system is broken," they wrote. "The review’s conclusions should lead to serious soul-searching among policy makers. So, too, should the story behind the review, illustrating as it does the entrenched flaws in the current system. Why did no one else demand this level of scrutiny before spending such huge sums of money on one drug?" they asked.
Dr. Godlee said that she and BMJ have been closely involved from the outset in the campaign for access to clinical trial data on oseltamivir. She coedited a book on peer review with one of the Cochrane authors, Dr. Tom Jefferson. She and BMJ work closely with another of the Cochrane authors, Carl Heneghan, on jointly hosted conferences. She recently recruited a third Cochrane author, Peter Doshi, to the staff of BMJ as an associate editor. She was not directly involved in the decisions to accept the neuraminidase inhibitor papers for publication in BMJ but will undoubtedly have communicated to her editorial colleagues her keenness that BMJ should publish them if at all possible.
*This article was updated April 10, 2014.
On Twitter @mitchelzoler
This publication of the most recent iteration of Cochrane reviews on the benefits and harms of oseltamivir and zanamivir marks the first time that reviews of these products included information from all the pertinent clinical trials conducted by the manufacturers. With these comprehensive new reviews based on all the data, the perspective on these drugs has changed substantially. With all the evidence available from treatment and prophylaxis studies it has become clear that convincing trial evidence of a reduction in the risk of hospitalization or complications is lacking.
In addition, the reviews found that oseltamivir causes nausea and vomiting, and probably causes heachaches, renal problems, and psychiatric syndromes. Zanamivir had fewer adverse effects but also had no demonstrated effect on complications or hospitalizations. Zanamivir reduced the duration of symptoms by about half a day, but the reviewers found that it may be no better than other symptom-relief medications. For prophylaxis, zanamivir significantly reduced the risk of symptomatic influenza, but there was heterogeneity among the studies and sample sizes were small. In addition there was no difference in asymptomatic influenza.
Based on these findings it is difficult to conceive that many patients would actively seek these treatments. The benefits involve a shortening of symptoms that few patients would find worth the risk of incurring the harms of treatment. From a health-system perspective, enormous expenditures on these drugs do not appear to have commensurate benefit.
Despite questions raised several years ago about full transparency on the risks and benefits of these two drugs, the medical establishment embraced them. Governments stockpiled the drugs, presuming that their potential public-health benefit merited a substantial financial investment. During this period, when not all of the trial results were fully and widely available, the Centers for Disease Control and Prevention, the U.K. National Institute for Health Care Excellence, the American Academy of Pediatrics, and the World Health Organization all suggested that oseltamivir and zanamivir provided benefits with minimal risks.
Of primary importance for decision makers is that now, with all of the data available for others to evaluate, the knowns and unknowns can be laid out clearly and reveal the weakness of the evidentiary support for these products and what we need to learn about them in the future.
Dr. Harlan M. Krumholz is a cardiologist and professor of medicine and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn. He said that he has received research grants from Medtronic and Johnson & Johnson and that he chairs a scientific advisory board for UnitedHealthcare. He made these comments in an editorial (BMJ 2014;348:g2548 doi:10.1136/bmj.g2548).
This publication of the most recent iteration of Cochrane reviews on the benefits and harms of oseltamivir and zanamivir marks the first time that reviews of these products included information from all the pertinent clinical trials conducted by the manufacturers. With these comprehensive new reviews based on all the data, the perspective on these drugs has changed substantially. With all the evidence available from treatment and prophylaxis studies it has become clear that convincing trial evidence of a reduction in the risk of hospitalization or complications is lacking.
In addition, the reviews found that oseltamivir causes nausea and vomiting, and probably causes heachaches, renal problems, and psychiatric syndromes. Zanamivir had fewer adverse effects but also had no demonstrated effect on complications or hospitalizations. Zanamivir reduced the duration of symptoms by about half a day, but the reviewers found that it may be no better than other symptom-relief medications. For prophylaxis, zanamivir significantly reduced the risk of symptomatic influenza, but there was heterogeneity among the studies and sample sizes were small. In addition there was no difference in asymptomatic influenza.
Based on these findings it is difficult to conceive that many patients would actively seek these treatments. The benefits involve a shortening of symptoms that few patients would find worth the risk of incurring the harms of treatment. From a health-system perspective, enormous expenditures on these drugs do not appear to have commensurate benefit.
Despite questions raised several years ago about full transparency on the risks and benefits of these two drugs, the medical establishment embraced them. Governments stockpiled the drugs, presuming that their potential public-health benefit merited a substantial financial investment. During this period, when not all of the trial results were fully and widely available, the Centers for Disease Control and Prevention, the U.K. National Institute for Health Care Excellence, the American Academy of Pediatrics, and the World Health Organization all suggested that oseltamivir and zanamivir provided benefits with minimal risks.
Of primary importance for decision makers is that now, with all of the data available for others to evaluate, the knowns and unknowns can be laid out clearly and reveal the weakness of the evidentiary support for these products and what we need to learn about them in the future.
Dr. Harlan M. Krumholz is a cardiologist and professor of medicine and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn. He said that he has received research grants from Medtronic and Johnson & Johnson and that he chairs a scientific advisory board for UnitedHealthcare. He made these comments in an editorial (BMJ 2014;348:g2548 doi:10.1136/bmj.g2548).
This publication of the most recent iteration of Cochrane reviews on the benefits and harms of oseltamivir and zanamivir marks the first time that reviews of these products included information from all the pertinent clinical trials conducted by the manufacturers. With these comprehensive new reviews based on all the data, the perspective on these drugs has changed substantially. With all the evidence available from treatment and prophylaxis studies it has become clear that convincing trial evidence of a reduction in the risk of hospitalization or complications is lacking.
In addition, the reviews found that oseltamivir causes nausea and vomiting, and probably causes heachaches, renal problems, and psychiatric syndromes. Zanamivir had fewer adverse effects but also had no demonstrated effect on complications or hospitalizations. Zanamivir reduced the duration of symptoms by about half a day, but the reviewers found that it may be no better than other symptom-relief medications. For prophylaxis, zanamivir significantly reduced the risk of symptomatic influenza, but there was heterogeneity among the studies and sample sizes were small. In addition there was no difference in asymptomatic influenza.
Based on these findings it is difficult to conceive that many patients would actively seek these treatments. The benefits involve a shortening of symptoms that few patients would find worth the risk of incurring the harms of treatment. From a health-system perspective, enormous expenditures on these drugs do not appear to have commensurate benefit.
Despite questions raised several years ago about full transparency on the risks and benefits of these two drugs, the medical establishment embraced them. Governments stockpiled the drugs, presuming that their potential public-health benefit merited a substantial financial investment. During this period, when not all of the trial results were fully and widely available, the Centers for Disease Control and Prevention, the U.K. National Institute for Health Care Excellence, the American Academy of Pediatrics, and the World Health Organization all suggested that oseltamivir and zanamivir provided benefits with minimal risks.
Of primary importance for decision makers is that now, with all of the data available for others to evaluate, the knowns and unknowns can be laid out clearly and reveal the weakness of the evidentiary support for these products and what we need to learn about them in the future.
Dr. Harlan M. Krumholz is a cardiologist and professor of medicine and director of the Center for Outcomes Research and Evaluation at Yale University, New Haven, Conn. He said that he has received research grants from Medtronic and Johnson & Johnson and that he chairs a scientific advisory board for UnitedHealthcare. He made these comments in an editorial (BMJ 2014;348:g2548 doi:10.1136/bmj.g2548).
A new systematic review of clinical studies of the oral anti-influenza drug oseltamivir that included a substantial amount of clinical data that were not part of previously published assessments showed that significant questions exist about oseltamivir’s role in treating and preventing influenza and in pandemic preparedness.
"Our results show that oseltamivir reduces the proportion of participants with symptomatic influenza when used for prophylaxis and has modest symptomatic effects when used for treatment, but it also causes nausea and vomiting and increases the risk of headache and renal and psychiatric syndromes," Tom Jefferson, Ph.D., wrote in an article published online on April 9 (BMJ 2014;348:g2545 doi:10.1136/bmj.g2545).
"We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug," concluded Dr. Jefferson, an epidemiologist with the Cochrane Library and head of the Italian Health Technology Assessment program in Rome, and his coauthors. "The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling," they wrote.
A second, simultaneously-published study by the same Cochrane-based group using previously unavailable clinical-study data for zanamivir, an inhaled anti-influenza drug, found that, while zanamivir treatment safely reduced by half a day the time to improvement in adults with symptomatic influenza, it had no effect on reducing the risk of complications of influenza, particularly pneumonia, or the risk for hospitalization or death, nor did it show any efficacy for reducing asymptomatic influenza and the subsequent risk for transmission (BMJ 2014;348:g2547 doi:10.1136/bmj.g2547).
The newly available data used by the Cochrane researchers in both reviews came from the manufacturers of the two drugs, Roche in the case of oseltamivir (Tamiflu) and GlaxoSmithKline in the case of zanamivir (Relenza). "Owing to the risk of reporting bias there are legitimate reasons to doubt the stated benefits of oseltamivir and the results of previous Cochrane reviews of neuraminidase inhibitors in adults and children," wrote Dr. Jefferson and his associates in the oseltamivir report.
"To tackle these problems, we have conducted a 4-year campaign to obtain full study reports of the oseltamivir trial program" as well as a parallel campaign that yielded full study reports for zanamivir. The 4-year campaign noted in the review involved an unusual collaboration between Dr. Jefferson and his Cochrane associates and editors at BMJ to put ongoing pressure on Roche and GlaxoSmithKline to promise and then follow through on delivering the full clinical reports from the drugs’ studies, data that finally reached the Cochrane researchers in late 2013.
"For the first time, a Cochrane review [on neuraminidase inhibitors] is based on all relevant full clinical study reports of a family of drugs, integrated by regulatory comments," the authors wrote. "We are pretty confident that this is the closest you’ll get to an unbiased data set," Dr. Jefferson added in an interview.
Despite the unprecedented completeness of the data behind the two reports and the questions they raise about the two drugs, Dr. Jefferson expressed skepticism that public health policy in the United States or United Kingdom will change as a result of the publications.
"I don’t think the people who made the decision to stockpile these drugs for influenza can make an objective decision with any new evidence. [Oseltamivir] was stockpiled but the evidence of its toxicity wasn’t ‘discovered’ by us. It’s been known since the 1990s. I’m skeptical [there will be change now] because the whole system needs to be overhauled. Individual physicians are very loath to prescribe these drugs. But for public health decisions I’m not holding my breath," Dr. Jefferson said.
In reply to a request for comment on the new reports, Gregory Härtl, a spokesperson for the WHO in Geneva, made this statement: "WHO has not seen the paper so cannot comment on specifics. We welcome a new and rigorous analysis of available data and look forward to consideration of its findings after it appears. WHO is committed to an evidence-based approach to determining the best advice for patient care."
Jason McDonald, a spokesperson for the Centers for Disease Control and Prevention in Atlanta made this statement: "CDC supports efforts to make public previously unpublished data from clinical trials. CDC and its advisory committee on immunization practices review all relevant scientific literature when making policy decisions about public health. Clinical trials are just one component of the overall body of scientific evidence that CDC and ACIP [Advisory Committee on Immunization Practices] review when making clinical recommendations on antiviral drugs. Observational trials are another such component, and CDC and ACIP have reviewed a considerable and ever growing number of such studies that show the benefits of antiviral medications in not only reducing and shortening symptoms of disease but also preventing hospitalizations and deaths, including in high risk children and adults. While there are limitations and possible biases that must be considered and controlled in such studies, these studies are easier to conduct due to ethical considerations and more of them are available.
"CDC welcomes the public release of all such data for academic review and discussion. These data have not changed CDC and ACIP’s recommendations for the clinical use of antivirals in the United States. Decisions regarding the purchase of antivirals for use in the U.S. Strategic National Stockpile in the event of an emergency are not made by CDC.
"It’s important to acknowledge that the neuraminidase inhibitor class of antiviral drugs, which includes Tamiflu and zanamivir, are a second line of defense against the flu. These drugs represent an important tool in the event of a flu outbreak, when a vaccine isn’t yet available. Such drugs are often the only treatment option available for flu, and while we all support the development of new and better drugs in the future, we must make the best use of the tools we have at our disposal to promote public health."
In June 2013, a multidisciplinary and international group of researchers developed an independent statistical plan for analyzing the full oseltamivir dataset with an eye toward determining the efficacy and safety of oseltamivir for treating and preventing influenza in both individual patients and for public health. The Multidisciplinary Group for Advice on Science (MUGAS) plans to present the results of its analysis in September at a meeting of the European Scientific Working Group on Influenza, according to Dr. Richard J. Whitely, professor and director of pediatric infectious diseases at the University of Alabama in Birmingham, and one of the organizers of the MUGAS project on oseltamivir.
Dr. Jefferson receives royalties from Blackwells and Il Pensiero Scientifico Editore, Rome, and gives interviews anonymously to market research companies about phase I or II pharmaceutical products. In 2011, he was an expert witness in a litigation case related to oseltamivir phosphate and in a labor case on influenza vaccines in health care workers in Canada. He has been a consultant for Roche, GlaxoSmithKline, and Sanofi-Synthelabo, and is currently a consultant for IMS Health.
BMJ support key
Dr. Jefferson called his 4-year effort to get full clinical-testing data on oseltamivir and zanamivir from the manufacturers a "campaign," and cited key support from the staff of the U.K.-based BMJ medical journal.
"If BMJ had not become involved neither Roche nor GlaxoSmithKline would have cooperated. BMJ pledged their support when we asked for the full clinical reports" in 2009, recalled Dr. Jefferson, who first raised the issue of getting wider data access and also led the Cochrane analysis on the new data.
The story began in 2009, during the H1N1 pandemic, which led to the Cochrane group’s receiving funding to perform an update to a neuraminidase-inhibitor review they had done in 2006. In the intervening years, information emerged suggesting a large cache of unpublished data had never been seen during the 2006 review, which focused on published materials.
"In 2011, we decided not to accept anything that had been published because it was biased," Dr. Jefferson said in an interview.
BMJ editors compiled details and links on this web page to the thrusts and parries between themselves and Cochrane staffers and the two companies involved, Roche and GlaxoSmithKline, during the several years it took to receive and evaluate the full data: www.bmj.com/tamiflu.
In an editorial accompanying the two reports from Cochrane on oseltamivir and zanamivir, Dr. Fiona Godlee, editor-in-chief at BMJ, Dr. Elizabeth Loder, another BMJ editor, and Dr. David Tovey, editor-in-chief of the Cochrane Library, called the Cochrane reviewers and their associates who authored the two papers "pioneers" for "navigating the uncharted territory" of the data analyses they performed using huge numbers of clinical study reports (BMJ 201;348:g2630 [doi: 10.1136/bmj.g2630]).
Dr. Loder, Dr. Tovey, and Dr. Godlee also said in their editorial that they saw the effort to get more data on the neuraminidase inhibitors as part of a larger effort to remake the way that drugs are assessed and reviewed.
The process required to obtain and analyze the neuraminidase inhibitor data showed "with greater clarity than ever that the current system is broken," they wrote. "The review’s conclusions should lead to serious soul-searching among policy makers. So, too, should the story behind the review, illustrating as it does the entrenched flaws in the current system. Why did no one else demand this level of scrutiny before spending such huge sums of money on one drug?" they asked.
Dr. Godlee said that she and BMJ have been closely involved from the outset in the campaign for access to clinical trial data on oseltamivir. She coedited a book on peer review with one of the Cochrane authors, Dr. Tom Jefferson. She and BMJ work closely with another of the Cochrane authors, Carl Heneghan, on jointly hosted conferences. She recently recruited a third Cochrane author, Peter Doshi, to the staff of BMJ as an associate editor. She was not directly involved in the decisions to accept the neuraminidase inhibitor papers for publication in BMJ but will undoubtedly have communicated to her editorial colleagues her keenness that BMJ should publish them if at all possible.
*This article was updated April 10, 2014.
On Twitter @mitchelzoler
A new systematic review of clinical studies of the oral anti-influenza drug oseltamivir that included a substantial amount of clinical data that were not part of previously published assessments showed that significant questions exist about oseltamivir’s role in treating and preventing influenza and in pandemic preparedness.
"Our results show that oseltamivir reduces the proportion of participants with symptomatic influenza when used for prophylaxis and has modest symptomatic effects when used for treatment, but it also causes nausea and vomiting and increases the risk of headache and renal and psychiatric syndromes," Tom Jefferson, Ph.D., wrote in an article published online on April 9 (BMJ 2014;348:g2545 doi:10.1136/bmj.g2545).
"We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug," concluded Dr. Jefferson, an epidemiologist with the Cochrane Library and head of the Italian Health Technology Assessment program in Rome, and his coauthors. "The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling," they wrote.
A second, simultaneously-published study by the same Cochrane-based group using previously unavailable clinical-study data for zanamivir, an inhaled anti-influenza drug, found that, while zanamivir treatment safely reduced by half a day the time to improvement in adults with symptomatic influenza, it had no effect on reducing the risk of complications of influenza, particularly pneumonia, or the risk for hospitalization or death, nor did it show any efficacy for reducing asymptomatic influenza and the subsequent risk for transmission (BMJ 2014;348:g2547 doi:10.1136/bmj.g2547).
The newly available data used by the Cochrane researchers in both reviews came from the manufacturers of the two drugs, Roche in the case of oseltamivir (Tamiflu) and GlaxoSmithKline in the case of zanamivir (Relenza). "Owing to the risk of reporting bias there are legitimate reasons to doubt the stated benefits of oseltamivir and the results of previous Cochrane reviews of neuraminidase inhibitors in adults and children," wrote Dr. Jefferson and his associates in the oseltamivir report.
"To tackle these problems, we have conducted a 4-year campaign to obtain full study reports of the oseltamivir trial program" as well as a parallel campaign that yielded full study reports for zanamivir. The 4-year campaign noted in the review involved an unusual collaboration between Dr. Jefferson and his Cochrane associates and editors at BMJ to put ongoing pressure on Roche and GlaxoSmithKline to promise and then follow through on delivering the full clinical reports from the drugs’ studies, data that finally reached the Cochrane researchers in late 2013.
"For the first time, a Cochrane review [on neuraminidase inhibitors] is based on all relevant full clinical study reports of a family of drugs, integrated by regulatory comments," the authors wrote. "We are pretty confident that this is the closest you’ll get to an unbiased data set," Dr. Jefferson added in an interview.
Despite the unprecedented completeness of the data behind the two reports and the questions they raise about the two drugs, Dr. Jefferson expressed skepticism that public health policy in the United States or United Kingdom will change as a result of the publications.
"I don’t think the people who made the decision to stockpile these drugs for influenza can make an objective decision with any new evidence. [Oseltamivir] was stockpiled but the evidence of its toxicity wasn’t ‘discovered’ by us. It’s been known since the 1990s. I’m skeptical [there will be change now] because the whole system needs to be overhauled. Individual physicians are very loath to prescribe these drugs. But for public health decisions I’m not holding my breath," Dr. Jefferson said.
In reply to a request for comment on the new reports, Gregory Härtl, a spokesperson for the WHO in Geneva, made this statement: "WHO has not seen the paper so cannot comment on specifics. We welcome a new and rigorous analysis of available data and look forward to consideration of its findings after it appears. WHO is committed to an evidence-based approach to determining the best advice for patient care."
Jason McDonald, a spokesperson for the Centers for Disease Control and Prevention in Atlanta made this statement: "CDC supports efforts to make public previously unpublished data from clinical trials. CDC and its advisory committee on immunization practices review all relevant scientific literature when making policy decisions about public health. Clinical trials are just one component of the overall body of scientific evidence that CDC and ACIP [Advisory Committee on Immunization Practices] review when making clinical recommendations on antiviral drugs. Observational trials are another such component, and CDC and ACIP have reviewed a considerable and ever growing number of such studies that show the benefits of antiviral medications in not only reducing and shortening symptoms of disease but also preventing hospitalizations and deaths, including in high risk children and adults. While there are limitations and possible biases that must be considered and controlled in such studies, these studies are easier to conduct due to ethical considerations and more of them are available.
"CDC welcomes the public release of all such data for academic review and discussion. These data have not changed CDC and ACIP’s recommendations for the clinical use of antivirals in the United States. Decisions regarding the purchase of antivirals for use in the U.S. Strategic National Stockpile in the event of an emergency are not made by CDC.
"It’s important to acknowledge that the neuraminidase inhibitor class of antiviral drugs, which includes Tamiflu and zanamivir, are a second line of defense against the flu. These drugs represent an important tool in the event of a flu outbreak, when a vaccine isn’t yet available. Such drugs are often the only treatment option available for flu, and while we all support the development of new and better drugs in the future, we must make the best use of the tools we have at our disposal to promote public health."
In June 2013, a multidisciplinary and international group of researchers developed an independent statistical plan for analyzing the full oseltamivir dataset with an eye toward determining the efficacy and safety of oseltamivir for treating and preventing influenza in both individual patients and for public health. The Multidisciplinary Group for Advice on Science (MUGAS) plans to present the results of its analysis in September at a meeting of the European Scientific Working Group on Influenza, according to Dr. Richard J. Whitely, professor and director of pediatric infectious diseases at the University of Alabama in Birmingham, and one of the organizers of the MUGAS project on oseltamivir.
Dr. Jefferson receives royalties from Blackwells and Il Pensiero Scientifico Editore, Rome, and gives interviews anonymously to market research companies about phase I or II pharmaceutical products. In 2011, he was an expert witness in a litigation case related to oseltamivir phosphate and in a labor case on influenza vaccines in health care workers in Canada. He has been a consultant for Roche, GlaxoSmithKline, and Sanofi-Synthelabo, and is currently a consultant for IMS Health.
BMJ support key
Dr. Jefferson called his 4-year effort to get full clinical-testing data on oseltamivir and zanamivir from the manufacturers a "campaign," and cited key support from the staff of the U.K.-based BMJ medical journal.
"If BMJ had not become involved neither Roche nor GlaxoSmithKline would have cooperated. BMJ pledged their support when we asked for the full clinical reports" in 2009, recalled Dr. Jefferson, who first raised the issue of getting wider data access and also led the Cochrane analysis on the new data.
The story began in 2009, during the H1N1 pandemic, which led to the Cochrane group’s receiving funding to perform an update to a neuraminidase-inhibitor review they had done in 2006. In the intervening years, information emerged suggesting a large cache of unpublished data had never been seen during the 2006 review, which focused on published materials.
"In 2011, we decided not to accept anything that had been published because it was biased," Dr. Jefferson said in an interview.
BMJ editors compiled details and links on this web page to the thrusts and parries between themselves and Cochrane staffers and the two companies involved, Roche and GlaxoSmithKline, during the several years it took to receive and evaluate the full data: www.bmj.com/tamiflu.
In an editorial accompanying the two reports from Cochrane on oseltamivir and zanamivir, Dr. Fiona Godlee, editor-in-chief at BMJ, Dr. Elizabeth Loder, another BMJ editor, and Dr. David Tovey, editor-in-chief of the Cochrane Library, called the Cochrane reviewers and their associates who authored the two papers "pioneers" for "navigating the uncharted territory" of the data analyses they performed using huge numbers of clinical study reports (BMJ 201;348:g2630 [doi: 10.1136/bmj.g2630]).
Dr. Loder, Dr. Tovey, and Dr. Godlee also said in their editorial that they saw the effort to get more data on the neuraminidase inhibitors as part of a larger effort to remake the way that drugs are assessed and reviewed.
The process required to obtain and analyze the neuraminidase inhibitor data showed "with greater clarity than ever that the current system is broken," they wrote. "The review’s conclusions should lead to serious soul-searching among policy makers. So, too, should the story behind the review, illustrating as it does the entrenched flaws in the current system. Why did no one else demand this level of scrutiny before spending such huge sums of money on one drug?" they asked.
Dr. Godlee said that she and BMJ have been closely involved from the outset in the campaign for access to clinical trial data on oseltamivir. She coedited a book on peer review with one of the Cochrane authors, Dr. Tom Jefferson. She and BMJ work closely with another of the Cochrane authors, Carl Heneghan, on jointly hosted conferences. She recently recruited a third Cochrane author, Peter Doshi, to the staff of BMJ as an associate editor. She was not directly involved in the decisions to accept the neuraminidase inhibitor papers for publication in BMJ but will undoubtedly have communicated to her editorial colleagues her keenness that BMJ should publish them if at all possible.
*This article was updated April 10, 2014.
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FROM BMJ
Key clinical point: The benefit of oseltamivir may not outweigh the risks for influenza prophylaxis or for treatment. While zanamivir reduced the length of influenza symptoms, it did not reduce the rate of complications.
Major finding: New clinical data on safety and efficacy of oseltamivir show that in prophylaxis trials, it reduced symptomatic influenza by 55% and zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by an average 14.4 hours, raising questions on risk-to-benefit of both drugs.
Data source: Review of 20 clinical studies of oseltamivir and 26 studies of zanamivir.
Disclosures: Dr. Jefferson receives royalties from Blackwells and Il Pensiero Scientifico Editore, Rome, and gives interviews anonymously to market research companies about phase I or II pharmaceutical products. In 2011, he was an expert witness in a litigation case related to oseltamivir phosphate and in a labor case on influenza vaccines in health care workers in Canada. He has been a consultant for Roche, GlaxoSmithKline, and Sanofi-Synthelabo, and is currently a consultant for IMS Health.