NICE’s  latest technology appraisal of the  flu antiviral drugs (amantadine, oseltamivir and zanamivir), published in February 2009  marks the sixth time these drugs have been considered. The timelines are  shown below.

In brief NICE has taken and maintained a strong position against the use of these drugs except for tightly defined at risk groups. What  interests me is the arguments that have been used to show that these drugs are not cost effective treatments  for healthy people. These arguments I think hinge on assumptions which largely lack evidence.

The cost per QALY (or QADay) calculation are fairly simple as follows, with  figures I have taken from the most recent  NICE appraisal. Both zanamivir and oseltamivir cost around £16. On average and taken within 48 hours of symptom onset, when influenza virus A or B is circulating, they reduce the  number of days before return to normal activities  by around 1. If the QALY loss due to having symptoms is 0.5, the cost per QALY would be £32 (16/0.5). Factor in the probability of 0.5 that symptoms are not flu and the cost per QALY doubles to £64.(16/0.5/0.5) Compare this with NICEs £20k/QALY threshold (=£55 per QADay) rising to £82 per QADay at the £30k threshold. This  crude calculation puts these drugs between  NICE’s upper and lower thresholds. This is why two other considerations mattered, one which reduces,  the other which increases,  the cost per QADay.

If one assumes that successful treatment with an antiviral  averts deaths (such as post influenza pneumonia) and associated hospitalisations, then the QADays would be increased and the cost  reduced. Although the number of deaths is unknown and  might well be small, the effect could be considerable. The cost per QALY for zanamivir for healthy adults fell from £30k to £8k when hospital admissions and deaths were included in NICE’s 2003 appraisal.

Against this the Appraisal Committee worried about the effect that making the drugs available might have on GP consultations. This could increase the costs and reduce the probability that the symptoms really were influenza. Again the numbers are lacking but the Committee considered that a rise of between 5% -15% was likely. This put the cost per QALY back up from £8k to  £27k in NICE’s 2003 appraisal.

In its 2009 appraisal the Committee went one ingenious  step further – it changed the Quality of Life loss due to influenza symptoms from 0.5 to 0.22 on the basis that the reduction in days with symptoms was likely to  be at the end of the episode when symptoms were likely to be less severe.  When hospitalisations and  mortality benefits were excluded this resulted in a cost per QALY  from £40k to £66k. On this basis it concluded that oseltamivir and zanamivir for the treatment of influenza in otherwise healthy adults would not be a cost effective use of NHS resources.

Several points strike me as interesting:

• The results hinge on assumptions to do with mortality, increased GP consultations and the quality of life loss due to symptoms in the last day of the episode,
• Very few data are available to support these assumptions, a position that has not changed over the decade since NICE first appraised these drugs
• That some of the data gaps are more researchable than others, such as the the quality of life loss due to flu symptoms. The mortality gain due to use of these drugs and the increase in GP consultations should the drugs be available on the NHS are much less easy to research.
• The lack of evidence for some of NICE’s consideration should be set against the almost complete lack of evidence supporting  the government decision in 2006 to  purchase an almost 15 million dose stockpile of oseltamivir for use in the event of a flu epidemic.

Timeline of 6 NICE appraisals of influenza antivirals:

• 1999 Fastrack appraisal of zanamivir: should not be prescribed
• 2000 Appraisal of zanamivir: recommended only for at risk adults who present within 36 hours
• 2003 Appraisal of zanamivir, oseltamivir and amantadine: zanamivir and oseltamivir recomemended only for people at risk (over 65 or have one of list of chronic diseases)
• 2003 Appraisal of oseltamivir and amantadine for the prophylaxis of influenza: oseltamivir recommended only for at risk groups)
• 2008 Appraisal of zanamivir, oseltamivir and amantadine for prophylaxis
• Appraisal of zanamivir, oseltamivir and amantadine for treatment of influenza.

James Raftery is a health economist with several decades’ experience of the NHS. He is professor of health technology assessment at Southampton University. A keen “NICE watcher,” he has provided economic input to technical assessment reports for NICE but has never been a member of any of its committees. The opinions expressed here are his personal views. He welcomes comments to his blog.