Effect of influenza treatment with oseltamivir on health outcome and costs in otherwise healthy children Reisinger K, Greene G, Aultman R, Sander B, Gyldmark M Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The use of oseltamivir for the treatment of influenza in otherwise healthy children. Type of intervention Treatment. Economic study type Cost-effectiveness analysis and cost-utility analysis. Study population The study population comprised otherwise healthy children aged 1 to 12 years, who presented within 48 hours of illness onset with an oral or otic temperature of at least 37.8 degrees C and at least one respiratory symptom (cough or coryza). Setting The setting was primary care. The clinical study was conducted in the USA and Canada. The economic analysis was based on UK data. Dates to which data relate The clinical study was conducted in 1998/1999. Additional effectiveness data were derived from literature published between 1996 and 2003. The resource use data were based on 1997 published data. The price year was 2002. Source of effectiveness data The effectiveness data were mainly obtained from a single study, with additional data derived from a review or synthesis of completed studies. Some estimates of effectiveness were based on opinion. Study sample Much of the effectiveness data used in the economic model were taken from a clinical trial. The initial study sample consisted of 698 patients presenting at the sites participating in the trial, who met the inclusion criteria. Three patients were withdrawn before taking any study medication. Influenza was confirmed in 452 (65%) of the remaining 695 patients. Of these, 235 received placebo and 217 received oseltamivir. Further details are provided elsewhere (see Other Publications of Related Interest). Study design The study was a randomised, double-blind, placebo-controlled multi-centre trial that was conducted during the 1998/1999 influenza season in the USA and Canada. The end point of the analysis was "return to normal health and Page: 1 / 7
activity (NHA)". Data for this end point were available for 225 (out of 235) children in the placebo group and 209 (out of 217) children in the oseltamivir group. Analysis of effectiveness The analysis of the clinical study was based on the intent-to-treat infected population, defined as those patients taking at least one dose of study medication and having laboratory-confirmed influenza. The primary outcome assessed, which was used in the economic analysis, was the time to return to NHA. This was defined as the time to return to the preinfluenza normal health and activity status. The groups appear to have been comparable at baseline. No further adjustments for confounding factors were reported. Effectiveness results The median time to return to NHA for children aged 1 to 12 years was 67.1 hours (range: 0.0-645.0) for the oseltamivir group, and 111.7 hours (range: 0.0-638.3) for the placebo group. The median time to return to NHA was significantly reduced in the oseltamivir group compared with the placebo group by almost 2 days (44.6 hours or 40% reduction, p<0.0001). A sub-group analysis in children aged 1 to 5 years old showed that median time to return to NHA was 63.5 hours (range: 0.0-645.0) for the oseltamivir group and 121.3 hours (range: 0.0-638.3) for the placebo group. A significant reduction in the median time to return to NHA was also observed for this sub-group of children (reduction of 57.8 hours or 2.4 days, p=0.0003). Clinical conclusions Oseltamivir was effective in reducing the duration of influenza illness, as measured by "return to NHA", in otherwise healthy children. Modelling A decision-analytic model was developed to simulate the costs and effects of treating influenza in children. The decision point was the general practitioner (GP)'s decision as to whether to prescribe oseltamivir or to provide usual care when presented with a child, aged 1 to 12 years, with influenza-like illness symptoms. A sub-group analysis of children aged 1 to 5 years was also performed. It was assumed that all patients fully complied with treatment. The rate of influenza cases diagnosed correctly out of all influenza-like illness consultations (diagnostic certainty) was assumed to be 60% in the base-case analysis. The clinical pathway in the model covered complications of influenza such as otitis media, pneumonia and bronchitis, as well as mortality associated with influenza and its complications. Depending on the severity of the symptoms, the patients were treated at either an inpatient or outpatient setting. Outcomes assessed in the review The outcomes assessed were: the number of days to return to NHA after infection with influenza; the probabilities of complications such as otitis media and pneumonia; the probabilities of hospitalisation due to influenza and its complications; and the mortality due to influenza and its complications. These outcomes were assessed for the two interventions examined, oseltamivir and usual care, both for the group of children aged 1 to 12 years and the sub-group of children aged 1 to 5 years. Study designs and other criteria for inclusion in the review Page: 2 / 7
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Approximately 5 primary studies were included in the review. Methods of combining primary studies The results of the individual primary studies were not combined. Investigation of differences between primary studies Potential differences between the primary studies were not discussed. Results of the review For children aged 1 to 12 years: the mean number of days to return to NHA, starting from the onset of influenza symptoms, was 3.90 with oseltamivir and 5.36 under usual care; the probability of otitis media was 0.12 for oseltamivir and 0.21 for usual care; the probability of pneumonia was 0.0014 for oseltamivir and 0.0017 for usual care; the probability of hospitalisation due to influenza was 0.00174 for oseltamivir and 0.00323 for usual care; the probability of hospitalisation for pneumonia was 0.082 for usual care; the mortality rate due to influenza was 0.00002 for usual care; and the mortality rate due to complications of pneumonia was 0.0007 under usual care. For the sub-sample of children aged 1 to 5 years: the mean number of days to return to NHA was 3.93 under oseltamivir therapy and 5.95 under usual care; the probability of otitis media was 0.12 for oseltamivir and 0.31 for usual care; the probability of pneumonia was 0.0004 for oseltamivir and 0.0017 for usual care; the probability of hospitalisation due to influenza was 0.02613 for oseltamivir and 0.04839 for usual care; the probability of hospitalisation for pneumonia was 0.082 for usual care; Page: 3 / 7
the mortality rate due to influenza was 0.00002 for usual care; and the mortality rate due to complications of pneumonia was 0.0007 under usual care. Methods used to derive estimates of effectiveness Some estimates of effectiveness were based on authors' assumptions. Estimates of effectiveness and key assumptions Assumptions made in relation to the input parameters of effectiveness were as follows: the probability of hospitalisation and mortality due to pneumonia as a complication of influenza after treatment with oseltamivir were the same as those reported for usual care; the mortality due to influenza was reduced by 50% (was equal to 0.00001) with oseltamivir compared with usual care; the hospitalisation rates and mortality due to complications of bronchitis and otitis media were the same as those due to uncomplicated influenza. These assumptions referred to the whole of the patient population, as well as the sub-sample of children aged 1 to 5 years. Measure of benefits used in the economic analysis Two measures of benefit were used in the economic analysis. These were the number of days of NHA gained and the number of quality-adjusted life-years (QALYs) gained. Effects due to mortality (life-years gained) were discounted at an annual rate of 1.5%. QALY weights were derived from published literature. Clinical trial data were used to estimate the percentage improvement in quality of life between usual care and oseltamivir during the first 7 days of the influenza episode. Since no data on daily quality of life improvement existed for the paediatric population, it was assumed that children would experience the same daily increase in quality of life as was seen for otherwise healthy adults. Direct costs The direct costs comprised health service costs. These covered the costs of visits to GPs and specialists, oseltamivir, antibiotics for the treatment of complications, prescriptions, diagnostic tests (excluding rapid flu tests) and hospitalisation. Only the unit costs of these cost elements were reported; the resources required were not provided. Resource use was based on the US National Ambulatory Medical Care Survey (1997), and was validated with a UK health economics expert. The unit costs were taken from UK databases. The total costs were derived using modelling. Year 2002 prices were used. Discounting was not applied since the costs were incurred during a short time (less than one year). Statistical analysis of costs The costs were treated deterministically. No statistical analysis of the costs was undertaken. Indirect Costs The indirect costs were not included in the analysis. Currency UK pounds sterling (). Page: 4 / 7
Sensitivity analysis Because of the uncertainty in the model structure and key model parameters, a probabilistic sensitivity analysis was performed using first- and second-order Monte Carlo simulation to estimate the variation in cost-effectiveness and costutility results. Distributions were attached to complications, hospitalisation rates, mortality, duration of illness, and costs for second-order Monte Carlo simulations. One-way sensitivity analyses were also conducted to assess the robustness of the results under different scenarios. For example, using various rates of diagnostic accuracy, assuming that some children start treatment too late to receive its benefits, using a lower hospitalisation rate for children aged 1 to 5 years, and excluding all effects of treatment on complications, hospitalisations and mortality. Estimated benefits used in the economic analysis The results were not reported disaggregated. The total benefits associated with each of the interventions assessed were not provided. Cost results The results were not presented disaggregated. The total costs associated with each of the interventions assessed were not reported. Synthesis of costs and benefits The costs and benefits were combined in the form of incremental cost-effectiveness ratios (ICERs). Two ICERs were calculated, the cost per day of NHA gained and the cost per QALY gained. For the whole group of children aged 1 to 12 years, the ICERs of oseltamivir versus usual care were 9.52/day of NHA gained (range in probabilistic analysis: 6.88-13.61), and 11,173/QALY gained (range in probabilistic analysis: 1,818/QALY to usual care dominating). The results were sensitive to a low rate of diagnostic accuracy. When the diagnostic accuracy was set at 10%, the ICERs became 78.54/day of NHA gained and 118,669/QALY gained. In all other analyses, the cost-utility form of ICER remained under 30,000/QALY gained. The results for the sub-group of children aged 1 to 5 years were in a lower range than those for the total paediatric population: oseltamivir dominated usual care in the base-case analysis. According to the probabilistic analysis, this result ranged from oseltamivir dominating usual care, to an ICER of 9.06/day of NHA gained, or to usual care becoming the dominant option (when the QALY was considered a measure of benefit). In all analyses, the ICERs for this sub-population were generally more favourable than those for the whole study population. Authors' conclusions From the perspective of a health care payer, even under conservative assumptions, the treatment of influenza-infected children with oseltamivir was cost-effective. Oseltamivir was an effective treatment option for influenza in children aged at least 1 year, allowing them to return to normal health and activity (NHA) faster than they would with usual care alone. Oseltamivir had the potential to significantly reduce the indirect costs of influenza, by enabling parents or caregivers to return to work more quickly after caring for an infected child. CRD COMMENTARY - Selection of comparators The comparator in the study was usual care for influenza (see Hypothesis/Study Question). You should consider whether the comparator reflects routine practice in your own setting. Validity of estimate of measure of effectiveness The effectiveness data came mainly from a single study, with additional data derived from a review or synthesis of completed studies. The single study was a randomised controlled trial (RCT). This was appropriate for the study question, as wellconducted RCTs are considered to be the 'gold' standard when comparing different health interventions. The authors Page: 5 / 7
did not report the method of randomisation. The study sample appears to have been representative of the study population and the patient groups were shown to be comparable in terms of demographic and baseline characteristics. Appropriate statistical tests were performed to determine statistically significant differences between the groups. It was not stated whether a systematic review was undertaken and, since the methods used to find and select the primary studies and to extract the data were unclear, it is difficult to assess the validity of the estimates. There may be relevant studies that were not included. The results of the individual primary studies were not combined, and potential differences between the primary studies were not discussed. The authors made key assumptions in the structure of their model, and not all of these were justified with reference to the medical literature. These facts introduced uncertainty into the effectiveness results obtained. Validity of estimate of measure of benefit The estimation of benefits was modelled. The decision-analytic model used for this purpose was appropriate, as it simulated the clinical pathways following infection with influenza, including main complications and associated mortality, using probabilities mainly reported in the published literature. The authors did not provide any details of the clinical trial used to derive the quality of life weights. Validity of estimate of costs It was stated that the study adopted the perspective of a health care payer. All the cost categories relevant to this perspective were included in the analysis. The unit costs were reported in full but the resources used were not provided, and this hinders the reproducibility of the results. It was not stated whether distributions of the costs were used in the probabilistic sensitivity analysis. Discounting was not carried out, but it was unnecessary since the costs were incurred during a short time (less than a year). The year to which the prices referred was reported, which increases the generalisability of the results. Other issues The authors made appropriate comparisons of their findings with those of other studies. The issue of generalisability to other settings was not discussed. The authors reported several limitations to their analysis. First, the lack of epidemiological data in some areas related to influenza complications, and the subsequent use of assumptions regarding these areas in the model. Second, the ambiguous use of QALYs in the context of influenza. The results of the study were not presented disaggregated: costs and benefits associated with the treatment options were not reported separately, which hinders the interpretation of the results. Nevertheless, the authors' conclusions reflect the scope of the analysis. Implications of the study The authors acknowledged that control of influenza through vaccination of children remains the primary policy for annual influenza management. However, they recommended antiviral influenza treatment as a viable option in children at high risk of severe illness and complications, unvaccinated children and children with reduced response to vaccination, as well as in seasons with a poor match between the circulating strain and the vaccine. Source of funding Funded by F. Hoffman-La Roche Ltd. Bibliographic details Reisinger K, Greene G, Aultman R, Sander B, Gyldmark M. Effect of influenza treatment with oseltamivir on health outcome and costs in otherwise healthy children. Clinical Drug Investigation 2004; 24(7): 395-407 PubMedID 17516726 Page: 6 / 7
Powered by TCPDF (www.tcpdf.org) Other publications of related interest Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatric Infectious Disease Journal 2001;20:127-33. Indexing Status Subject indexing assigned by NLM AccessionNumber 22004001039 Date bibliographic record published 30/06/2005 Date abstract record published 30/06/2005 Page: 7 / 7