National Institute of Clinical Excellence. Review of TA158; Oseltamivir, amantadine and zanamivir for the prophylaxis of influenza, and TA168; Amantadine, oseltamivir and zanamivir for the treatment of influenza)

The paper stated: We consider that the results of the Cochrane update are unlikely to change the recommendations of TA158 and TA168.

• First, the population for whom oseltamivir and zanamivir are recommended by NICE is the ‘at-risk’ group as defined in TA158 and 168. The Cochrane update reports on evidence for healthy adults and children, without providing results for subgroups, including what could be considered as the ‘at-risk’ population.
• Second, although the effect sizes in terms of symptomatic benefits are perhaps a little lower than was assumed in the analyses performed for NICE in TA168, they are not inconsistent with the range of estimates applied in different scenarios explored for that guidance. In those scenarios more conservative symptomatic benefits (which appear comparable to those reported here) were applied, resulting in oseltamivir as still being cost-effective.
• Furthermore, the Committee noted that in all of the population subgroups, treatment with either antiviral drug was associated with reductions in the average duration of symptoms compared with placebo, although the difference was not statistically significant in all subgroups. The Committee acknowledged that the reduction in duration of symptoms was generally greater for the ‘at risk’ population compared with healthy populations. Page 3 of 16
• Third, although it is more difficult to compare inputs for complications given the different definitions employed in the Cochrane paper and the approach used in the economic model for TA168 (i.e. linking all complications via treatment effect on antibiotic use), the results presented in the Cochrane re view don’t appear to be particularly different to the inputs used for TA168, and hence it is considered unlikely that this would significantly alter the conclusions.
• Furthermore, excluding complications only made a difference when combined with changes to other assumptions (e.g. QoL) in themodel used for TA168. In these combined scenarios, the ICER increased to >£30k in the ‘otherwise healthy’ population (see Tables 7.30 and 7.31 page 193 of the Assessment Group report). Importantly, these scenarios remained below £30k in the at-risk populations. These scenarios were discussed in full by the committee and their position (i.e.complications less plausible for otherwise healthy adults) is stated in paragraphs 4.3.13-4.3.16 of the FAD.
• Finally, the Cochrane review reports an increase in adverse events of a neuropsychiatric nature in the trials for oseltamivir in adults.
• The Cochrane review reports that: ‘in prophylaxis trials of oseltamivi there was a significant increase in patients with psychiatric adverse events over the on and off treatment periods (RR 1.80, 95%CI 1.05 to 3.08, I2 statistic = 0%; RD 1.06%, 95%CI 0.07 to 2.76; NNTH = 94, 95% CI 36 to 1538)’. Such a result was not reported for the treatment trials of oseltamivir or for any of the trials with zanamivir. Although this is important new data, and potentially could be relevant to be considered in a technology appraisal, we consider it first and foremost something for the regulators to look at.
• Second, it is unclear what the signal for these adverse events is in the group of interest in TA158 ‘at risk patients’ as the Cochrane review only reports of ‘healthy adults’ in this respect.
• Third, even if this signal is exactly replicated in the at risk group, with the same intensity, and the same distribution over the various psychiatric conditions, it is difficult to be certain about the impact on the cost effectiveness of the drugs without performing the analyses. The signal is low for oseltamivir (2.20%), representing 44 events in 2000 subjects, compared with a comparably low signal for placebo (1.32%-19 events in 1434 subjects), leading to a small difference; 0.88% in favour of placebo. Finally, it is not
• clear what level of severity of depression-the main event in this category–was reported for patients in these trials, although it is reported by Cochrane that of the 66 events in this category, 12 were classified as ‘severe intensity’ (10 oseltamivir, 2 placebo)..Again, three respondents agreed with the proposal to move the guidance to the static list. Two respondents provided ‘no comment’, and the Cochrane Acute Respiratory Infections Group disagreed. On balance, NICE has come to the view that the guidance does not, at this stage, need reviewing