Guidelines on neuraminidase inhibitors in children are not supported by evidence
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《英国医生杂志》
EDITOR—Guidelines from the National Institute for Clinical Excellence (NICE) on the use of neuraminidase inhibitors recommend oseltamivir for the treatment of at risk children with influenza-like illness of fewer than 48 hours' duration—for example, those with underlying chronic respiratory disease.1 The drug is not recommended for otherwise healthy children.
In our systematic review on the use of neuraminidase inhibitors in children, however, we found no published studies on the effectiveness of oseltamivir in reducing the duration of illness in at risk, rather than healthy, children.2 Despite this, unpublished data from at risk children seem to exist and were made available by the manufacturers of oseltamivir during their application for European Marketing Authorisation for the drug. In the ensuing European Public Assessment Report, reference is made to results from 178 children with chronic asthma and confirmed influenza infection enrolled in study WV15759/WV15871.3 The stated difference in time to freedom from illness between children receiving placebo and children receiving oseltamivir is statistically non-significant, at only 10.3 hours (a reduction of 8%; P = 0.54).
The failure to publish study WV15759/WV15871 seems to be an example of publication bias. Furthermore, these unpublished data, although distributed to the European Agency for the Evaluation of Medicinal Products, seem not to have been made available to NICE. Certainly, the systematic review commissioned by NICE to inform their guidance, abbreviated in the BMJ, excluded the study because there were no data.4 5
In the absence of these data, and by assuming the benefits of neuraminidase inhibitors to be greatest in children at highest risk of complications of influenza, NICE has acted to focus the use of oseltamivir in children on those at risk—the very population for whom the evidence of benefit is weakest.
Mkael Symmonds, preregistration house officer
Department of Surgery, Ayr Hospital, Ayr KA6 6DX mkael@doctors.org.uk
Nicholas J Matheson, preregistration house officer
Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU
Anthony Harnden, university lecturer
Department of Primary Health Care, Institute of Health Sciences, Oxford OX3 7LF
Competing interests: None declared.
References
National Institute for Clinical Excellence. Technology appraisal guidance No 58. London: NICE, 2003. http://www.nice.org.uk/pdf/58_Flu_fullguidance.pdf
Matheson NJ, Symmonds-Abrahams M, Sheikh A, Shepperd S, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software
European Agency for the Evaluation of Medicinal Products. Tamiflu. European Public Assessment Report 2002. http://www.eudra.org/humandocs/humans/epar/tamiflu/tamiflu.htm
Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technology Assessment 2002. http://www.nice.org.uk/docref.asp?d=35650
Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner DA, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003;326: 1235-40.
In our systematic review on the use of neuraminidase inhibitors in children, however, we found no published studies on the effectiveness of oseltamivir in reducing the duration of illness in at risk, rather than healthy, children.2 Despite this, unpublished data from at risk children seem to exist and were made available by the manufacturers of oseltamivir during their application for European Marketing Authorisation for the drug. In the ensuing European Public Assessment Report, reference is made to results from 178 children with chronic asthma and confirmed influenza infection enrolled in study WV15759/WV15871.3 The stated difference in time to freedom from illness between children receiving placebo and children receiving oseltamivir is statistically non-significant, at only 10.3 hours (a reduction of 8%; P = 0.54).
The failure to publish study WV15759/WV15871 seems to be an example of publication bias. Furthermore, these unpublished data, although distributed to the European Agency for the Evaluation of Medicinal Products, seem not to have been made available to NICE. Certainly, the systematic review commissioned by NICE to inform their guidance, abbreviated in the BMJ, excluded the study because there were no data.4 5
In the absence of these data, and by assuming the benefits of neuraminidase inhibitors to be greatest in children at highest risk of complications of influenza, NICE has acted to focus the use of oseltamivir in children on those at risk—the very population for whom the evidence of benefit is weakest.
Mkael Symmonds, preregistration house officer
Department of Surgery, Ayr Hospital, Ayr KA6 6DX mkael@doctors.org.uk
Nicholas J Matheson, preregistration house officer
Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU
Anthony Harnden, university lecturer
Department of Primary Health Care, Institute of Health Sciences, Oxford OX3 7LF
Competing interests: None declared.
References
National Institute for Clinical Excellence. Technology appraisal guidance No 58. London: NICE, 2003. http://www.nice.org.uk/pdf/58_Flu_fullguidance.pdf
Matheson NJ, Symmonds-Abrahams M, Sheikh A, Shepperd S, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software
European Agency for the Evaluation of Medicinal Products. Tamiflu. European Public Assessment Report 2002. http://www.eudra.org/humandocs/humans/epar/tamiflu/tamiflu.htm
Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technology Assessment 2002. http://www.nice.org.uk/docref.asp?d=35650
Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner DA, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003;326: 1235-40.