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BMJ: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

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  • BMJ: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

    Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments
    BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2545 (Published 10 April 2014)
    Cite this as: BMJ 2014;348:g2545


    Tom Jefferson, reviewer1,
    Mark Jones, senior research fellow (biostatistics)2,
    Peter Doshi, assistant professor3,
    Elizabeth A Spencer, nutritional epidemiologist4,
    Igho Onakpoya, research fellow in evidence-based practice and pharmacovigilance4,
    Carl J Heneghan, professor4

    1Cochrane Acute Respiratory Infections Group, Via Puglie 23, 00187 Rome, Italy
    2School of Population Health, University of Queensland, Brisbane, Australia
    3Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
    4Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

    Correspondence to: T Jefferson jefferson.tom{at}gmail.com

    Accepted 3 April 2014

    Abstract

    Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments (“regulatory information”).

    Design Systematic review of regulatory information.

    Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.

    Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.

    Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.

    Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95&#37; confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval −0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for “pneumonia,” and no clinical study reports reported laboratory or diagnostic confirmation of “pneumonia.” The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two “pivotal” treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, −0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).

    Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

    full article


    http://www.bmj.com/content/348/bmj.g2545

  • #2
    Re: BMJ: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

    EDITORIAL


    Neuraminidase inhibitors for influenza
    BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2548 (Published 10 April 2014)
    Cite this as: BMJ 2014;348:g2548



    Harlan M Krumholz, Harold H Hines Jr professor of medicine

    1Department of Internal Medicine, Yale University School of Medicine New Haven, CT 06510, USA; Department of Health Policy and Management, Yale School of Public Health; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital

    harlan.krumholz{at}yale.edu

    The whole truth and nothing but the truth

    Informed choice requires comprehensive and credible information. Much of the rationale for the currently evolving movement to fully share data is to provide information for decision making, particularly in situations involving the need to balance the potential benefits and harms of medical products. This investment in data sharing is based on the premise that the value of the information from unavailable data is sufficiently meaningful to be worth the effort to make them available.1 Presumably, patients, with guidance from their doctors, might choose differently if data owners were to release all the information relevant to specific treatments and if independent scientists were able to properly analyze and communicate the results.

    The publication of the most recent iteration of Cochrane reviews on the benefits and harms of oseltamivir and zanamivir, two neuraminidase inhibitors approved for the treatment of influenza, marks the first time that reviews of these products included information from all the pertinent clinical trials conducted by the manufacturers.2 3 Prior reviews could consider only a proportion of the studies that scientists had conducted with the drugs, since many were unpublished or selectively published. As a result of having much data out of public view, the prior reviews expressed substantial uncertainty about the benefits and harms of these antiviral agents, which led to repeated requests for all data to be made available.4 5

    Even in the absence of full transparency regarding the risks and benefits of oseltamivir and zanamivir, the medical establishment embraced the drugs. Sales garnered billions of dollars. Moreover, governments stockpiled the drugs, presuming that their potential public health benefit merited the substantial investment. During this period, authoritative sources, based on a medical literature with less than all of the trial results, suggested that oseltamivir and zanamivir provided benefit with minimal risks. For example, the United States Centers for Disease Control and Prevention states: “For people with a high risk medical condition, treatment with an antiviral drug can mean the differences between having a milder illness instead of a very serious illness that could result in a hospital stay.” The agency further states that the drugs work best if started within two days of illness, but “starting them later can still be helpful, especially if the sick person has a high risk health condition or is very sick from the flu.” The National Institute for Health and Care Excellence (NICE) of the United Kingdom states that oseltamivir and zanamivir are indicated for patients who have a high risk of complications.6 7 The recommendations from the American Academy of Pediatrics state: “Investigators have consistently found that timely oseltamivir treatment can reduce the risk of complications, including those resulting in hospitalization and death.”8 The World Health Organization lists oseltamivir as an essential medicine for adults and children.9 Interestingly, the US Food and Drug Administration, which did have access to all the trial data, required the label for oseltamivir to indicate that it has not been shown to prevent bacterial infections.10

    With the comprehensive new reviews based on all the data, the perspective has changed substantially.2 3 The previous findings that symptoms can be shortened by about half a day (from about a week in the placebo group) remain, but, with all the evidence available from treatment and prophylaxis studies, it has become clearer that convincing clinical trial evidence of a reduction in the risk of hospitalization or complications is lacking. Moreover, the reviewers found that oseltamivir causes nausea and vomiting and increases the risk of headaches, renal problems, and psychiatric syndromes. Zanamivir had fewer adverse effects but also had no demonstrated effect on complications or hospitalizations. The drug did reduce 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. There were similar findings for oseltamivir, and the investigators noted that there was partial reporting of influenza-like illness. The findings are hardly definitive.

    Unless other evidence or analyses demonstrate more conclusive proof of benefit over harm, it is difficult to conceive that many patients would actively seek treatment. The benefits involve a shortening of symptoms that few patients would find worth the risks of incurring the harms of treatment. From a health system perspective, the enormous expenditures do not appear to have commensurate benefit.

    Unfortunately, even with all the existing data in view, many questions linger, which is remarkable given that the drugs have been approved for 15 years. A large, definitive set of clinical trials performed by an independent group and focused on patient groups that are currently understudied, including children, has yet to be conducted. Until it is, we know too little about the heterogeneity of effects and whether there are people who are more likely to benefit and less likely to be harmed. In most of the studies, the number of events is too small to assess heterogeneity—and even with pooling all the subjects, the confidence intervals are wide. There is some question over whether complications were systematically collected or reported in many trials. Moreover, the burden of the complications is not well characterized, making it difficult to determine how patients experience them. The usefulness for prophylaxis is uncertain given the size of the studies. Finally, the incremental benefit of these drugs compared with other symptom relief medications is based on only a small number of studies. Given the number of people each year affected by influenza, it would seem very possible to obtain answers to these questions in one winter.

    For now, health professionals can communicate the available evidence to anyone contemplating taking oseltamivir and zanamivir for prophylaxis or treatment, with confidence that nothing is hidden from view. Many patients may consider the risk of adverse effects to more than offset the prospect of shortening symptoms by half a day. For those who pay out of pocket, the additional costs may also be a deterrent. 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, revealing the weakness of the evidentiary support for these products and what exactly we need to learn for the future.
    Notes

    Cite this as: BMJ 2014;348:g2548
    Footnotes

    Research doi:, doi:10.1136/bmj.g2545 10.1136/bmj.g2547

    Funding: I am supported by grant U01 HL105270-04 (Center for Cardiovascular Outcomes Research at Yale University) from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, USA.

    Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: I have received research grants from Medtronic and from Johnson & Johnson, through Yale University, to develop methods of clinical trial data sharing; I am chair of a cardiac scientific advisory board for UnitedHealth.

    References


    Ross JS, Krumholz HM. Ushering in a new era of open science through data sharing: the wall must come down. JAMA2013;309:1355-6.
    OpenUrlCrossRefMedlineWeb of Science

    Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports. BMJ2014;348:g2547.
    OpenUrlAbstract/FREE Full Text

    Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ2014;348:g2545.
    OpenUrlAbstract/FREE Full Text

    Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ2009;339:b5106.
    OpenUrlAbstract/FREE Full Text

    Krumholz HM, Jackevicius CA, Ross JS. Tamiflu: 14 flu seasons and still questions. BMJ2013;346:f547.
    OpenUrlFREE Full Text

    National Institute for Health and Care Excellence. Oseltamivir, amantadine and zanamivir for the prophylaxis of influenza (including a review of TA67). (Technology appraisal 158.) 2008. www.nice.org.uk/TA158.

    National Institute for Health and Care Excellence. Amantadine, oseltamivir and zanamivir for the treatment of influenza (review of existing guidance No 58). (Technology appraisal 168.) 2009. www.nice.org.uk/TA168.

    Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2012-2013. Pediatrics2012;130:780-92.
    OpenUrlAbstract/FREE Full Text

    World Health Organization. WHO model lists of essential medicines. 2013. http://www.who.int/medicines/publica...lmedicines/en/.

    US Food and Drug Administration. Drugs @ FDA: FDA approved drug products. http://www.accessdata.fda.gov/script...tory#labelinfo

    http://www.bmj.com/content/348/bmj.g2548

    Comment


    • #3
      BMJ. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

      [Source: British Medical Journal, full page: (LINK). Abstract, edited.]
      Research


      Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

      <CITE><ABBR>BMJ </ABBR>2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2547 (Published 10 April 2014) / Cite this as: <ABBR>BMJ</ABBR> 2014;348:g2547</CITE>
      <CITE></CITE>
      Carl J Heneghan, 1, Igho Onakpoya, 1, Matthew Thompson, Helen D Cohen 2, Elizabeth A Spencer, 1, Mark Jones, 3, Tom Jefferson, 4

      Author Affiliations: <SUP>1</SUP>Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK <SUP>2</SUP>Department of Family Medicine, University of Washington, Seattle, USA <SUP>3</SUP>School of Population Health, University of Queensland, Brisbane, Australia <SUP>4</SUP>Cochrane Acute Respiratory Infections Group, Via Puglie 23, 00187 Rome, Italy

      Correspondence to: C J Heneghan carl.heneghan@phc.ox.ac.uk

      Accepted 4 April 2014


      Abstract

      Objectives

      To describe the potential benefits and harms of zanamivir.


      Design

      Systematic review of clinical study reports of randomised placebo controlled trials and regulatory information


      Data sources

      Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.


      Eligibility criteria for selecting studies

      Randomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza.


      Main outcome measures

      Time to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population.


      Results

      We included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I<SUP>2</SUP>=9%), which equates to an average 14.4 hours’ reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, −0.73% to 0.70%) or radiologically confirmed pneumonia (−0.06%, −6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, −1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, −1.10% to 1.10%) or in households (1.32%, −2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086).


      Conclusions

      Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.


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      Comment


      • #4
        Re: BMJ: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

        BMJ. 2014 Apr 10;348:g2263. doi: 10.1136/bmj.g2263.
        Multisystem failure: the story of anti-influenza drugs.
        Jefferson T1, Doshi P.


        http://www.ncbi.nlm.nih.gov/pubmed/24721793

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