Influenza (prophylaxis) - amantidine, oseltamivir and zanamivir: appraisal consultation document
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza (including a review of NICE technology appraisal guidance 67)
|
The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a multiple technology appraisal of oseltamivir, amantadine and zanamivir and provide guidance on their use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of oseltamivir, amantadine and zanamivir. This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk Note that this document does not constitute the Institute's formal guidance on oseltamivir, amantadine and zanamivir. The recommendations made in section 1 are preliminary and may change after consultation. The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
The key dates for this appraisal are: Closing date for comments: 9 June 2008 5pm Second Appraisal Committee meeting: 19 June 2008 Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B. |
| Note that this document does not constitute the Institute's formal guidance on these technologies. The recommendations made in section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| This guidance has been prepared in the expectation that vaccination against influenza is undertaken in accordance with national guidelines. Vaccination has been established as the first-line intervention to prevent influenza and its complications, and the use of drugs described in this guidance should not in any way detract from efforts to ensure that all eligible people receive vaccination. | |
| This guidance does not cover the circumstances of a pandemic, impending pandemic, or a widespread epidemic of a new strain of influenza to which there is little or no community resistance. | |
| 1.1 |
Oseltamivir and zanamivir are recommended, within their marketing authorisations, for the post-exposure prophylaxis of influenza if all of the following circumstances apply.
|
| 1.2 | The choice of either oseltamivir or zanamivir in the circumstances described in 1.1 should be determined by the healthcare professional in consultation with patients and carers. The decision should take into account preferences regarding the delivery of the drug and potential adverse effects and contraindications. If all other considerations are equal, the drug with the lowest acquisition cost should be used. |
| 1.3 |
For the purpose of this guidance, people at risk are defined as those who have one of more of the following:
|
| 1.4 | Exposure to influenza-like illness is defined as being in close contact within the same household with a person who has had recent symptoms of influenza. |
| 1.5 |
People who are not effectively protected by vaccination include:
|
| 1.6 | When surveillance schemes do not indicate that influenza virus is at the level of 'normal seasonal activity' (i.e. out of season), oseltamivir and zanamivir may still used as options for post-exposure prophylaxis in vaccinated or unvaccinated individuals living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence, of infection with influenza in the incident case or cases. |
| 1.7 | Oseltamivir and zanamivir are not recommended for seasonal prophylaxis. |
| 1.8 | Amantadine is not recommended for the prophylaxis of influenza. |
| 2 | Clinical need and practice |
| 2.1 | Influenza is an acute infection of the respiratory tract caused by the influenza A and B viruses. The symptoms of influenza are a fever accompanied by respiratory symptoms such as sneezing, coughing, runny nose and sore throat and systemic symptoms such as malaise, myalgia, chills and headaches. Gastrointestinal symptoms such as nausea, vomiting and diarrhoea are also common. |
| 2.2 | Influenza occurs in a seasonal pattern with epidemics in the winter months, typically between December and March. The illness is highly contagious and is spread from person to person by droplets of respiratory secretions produced by sneezing and coughing. Influenza is commonly transmitted through household contacts, with the highest attack rates in children. People who live in residential accommodation and those who work in healthcare settings are at a higher risk of infection. |
| 2.3 | Influenza infection is usually self-limiting and lasts for 3-4 days, with some symptoms persisting for 1-2 weeks. The severity of the illness can vary from asymptomatic infection to life-threatening complications. The most common complications are secondary bacterial infections such as otitis media, pneumonia and bronchitis. Other respiratory complications include viral pneumonia and exacerbation of chronic respiratory diseases such as asthma. Non-respiratory complications include encephalopathy, transverse myelitis, pericarditis, myocarditis, Reye's syndrome and toxic shock syndrome. Complications are more common in 'at-risk' groups, including people aged 65 and older; infants (particularly infants with congenital abnormalities); people with chronic respiratory, cardiovascular, neurological, liver or renal disease; people with diabetes mellitus and people who are immunosuppressed. |
| 2.4 | Influenza-like illness, which can be caused by a variety of infectious agents, is a clinical diagnosis made on the basis of symptoms including fever, cough, sore throat, headache and myalgia. The causative agent for an influenza-like illness cannot be determined clinically and diagnosis requires laboratory testing. Influenza can be confirmed by viral culture or polymerase chain reaction (PCR) of nose, throat or nasopharyngeal secretions, or by rising serum antibody titres. Influenza activity is monitored through surveillance schemes, which record the number of new general practitioner (GP) consultations for influenza-like illness per week per 100,000 population. In England, normal seasonal activity is 30-200 such consultations, with greater than 200 defined as an epidemic. In Wales, the corresponding figures are 25-100, and greater than 400. In addition there are virological monitoring schemes based on the isolation of the virus from clinical specimens. The incidence of influenza is called the attack rate. It is expressed as the proportion of people at risk who develop the disease during the period under consideration. The influenza attack rate depends on the circulating level of influenza. It is estimated that yearly influenza epidemics in the UK cause between 12,000 and 13,800 deaths. |
| 2.5 | Influenza is a self-limiting illness; management is supportive and consists of relieving symptoms while awaiting recovery. For people in at-risk groups who can start therapy within 48 hours of the onset of an influenza-like illness, treatment with the antiviral drugs oseltamivir or zanamivir is recommended in line with 'Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza' (NICE technology appraisal guidance 58). All people, but especially those in at-risk groups, need to be monitored for the development of complications. Complications require specific management, and antibiotics are used for secondary bacterial infections. |
| 2.6 | Prevention of influenza is most effectively achieved by vaccination. In the UK, the Department of Health currently recommends that people who are at risk of influenza infection or complications are vaccinated at the beginning of each winter. Such people are those with chronic respiratory, cardiovascular, renal, liver or neurological disease, people with diabetes, people who are immunosuppressed, people aged 65 and older, people who work or live in residential care facilities, carers of at-risk people, healthcare and other essential workers and poultry workers. |
| 2.7 | Antiviral drugs are also used for the prevention of influenza. They are given to people who have been in contact with a person with influenza-like illness (post-exposure prophylaxis) and are given in the absence of known contact but when it is known that influenza is circulating in the community (seasonal prophylaxis). Seasonal prophylaxis is carried out for longer periods to cover the duration of the influenza season. Seasonal prophylaxis is considered in exceptional situations such as an antigenic mismatch between circulating strains of the influenza virus and that used for vaccination which would mean that at-risk people are not adequately protected by vaccination. Prophylaxis may also be used to control outbreaks of influenza within a residential community. |
| 3 | The technologies |
| Oseltamivir | |
| 3.1 | Oseltamivir (Tamiflu, Roche) is a neuraminidase inhibitor that is active against influenza A and B. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a marketing authorisation for post-exposure prophylaxis in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community. The appropriate use of oseltamivir for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g., in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older. For post-exposure prophylaxis, oseltamivir should be started within 48 hours of contact with an index case of influenza-like illness and continued for 10 days. For seasonal prophylaxis, oseltamivir is given for up to 6 weeks. Oseltamivir is administered orally. |
| 3.2 | Adverse effects with oseltamivir include gastrointestinal symptoms, bronchitis and cough, dizziness and fatigue and neurological symptoms such as headache, insomnia and vertigo. Skin rashes and allergic reactions and, rarely, hepato-biliary system disorders have been reported. Convulsions and psychiatric events, mainly in children and adolescents, have also been reported but a causal link has not been established. For full details of adverse effects and contraindications, see the summary of product characteristics. Viral resistance to oseltamivir has been documented. |
| 3.3 | Oseltamivir costs £16.36 for a 10-day course for an adult (excluding VAT; 'British national formulary' [BNF] edition 54). Costs may vary in different settings because of negotiated procurement discounts. |
| Amantadine | |
| 3.4 | Amantadine (Lysovir, Symmetrel, Alliance Pharmaceuticals) acts against influenza A by inhibiting an ion channel and blocking viral replication. The marketing authorisation recommends amantadine prophylactically in cases particularly at risk. This can include those with chronic respiratory disease or debilitating conditions, the elderly and those living in crowded conditions. It can also be used for individuals in families where influenza has already been diagnosed, for control of institutional outbreaks or for those in essential services who are unvaccinated or when vaccination is unavailable or contra-indicated.. It is also recommended as post-exposure prophylaxis in conjunction with inactivated vaccine during an outbreak until protective antibodies develop, or in patients who are not expected to have a substantial antibody response (immunosuppression). Amantadine is licensed for use in children aged 10 years or older. The summary of product characteristics states that treatment is recommended for as long as protection from infection is required and that in most instances this is expected to be for 6 weeks. In clinical practice this corresponds to its use as seasonal prophylaxis. For post-exposure prophylaxis, amantadine is usually given for 4-5 days. Amantadine is administered orally. |
| 3.5 | The adverse effects of amantadine are often mild and transient. The most commonly reported effects were gastro-intestinal disturbances such as anorexia and nausea and CNS effects such as loss of concentration, dizziness, agitation, nervousness, depression, insomnia, fatigue, weakness and myalgia. Central nervous system effects are most common in older people. For full details of adverse effects and contraindications, see the summary of product characteristics. |
| 3.6 | Amantadine costs £2.40 for five capsules (100 mg each), £4.80 for 14 capsules and £5.55 for 150 ml syrup (50 mg/5 ml) (excluding VAT; 'British national formulary' [BNF] edition 54). Costs may vary in different settings because of negotiated procurement discounts. |
| Zanamivir | |
| 3.7 | Zanamivir (Relenza, GlaxoSmithKline) is a neuraminidase inhibitor that is active against influenza A and B. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a marketing authorisation for post-exposure prophylaxis of influenza A and B in adults and children ( 5 years and older) following contact with a clinically diagnosed case in a household . In exceptional circumstances, zanamivir may be considered for seasonal prophylaxis of influenza A and B during a community outbreak (e.g. in case of a mismatch between circulating and vaccine strains and a pandemic situation). For post-exposure prophylaxis zanamivir should be initiated within 36 hours of contact with an index case of influenza-like illness and continued for 10 days. For seasonal prophylaxis, zanamivir is given for up to 28 days. Zanamivir is administered by oral inhalation using an inhaler device. |
| 3.8 | Adverse effects associated with zanamivir are rare. They include bronchospasm and allergic phenomena. For full details of adverse effects and contraindications, see the summary of product characteristics. |
| 3.9 | The cost of zanamivir was reduced during the course of the appraisal to £16.36 for a 10-day course. The price of zanamivir currently listed in the BNF is £24.55 for a 10-day course (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts. |
| 4 | Evidence and interpretation |
| The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). | |
| 4.1 | Clinical effectiveness |
| 4.1.1 | The Assessment Group conducted a systematic search for randomised controlled trials (RCTs) conducted in people in contact with clinically diagnosed influenza or people for whom seasonal prophylaxis would be appropriate (exceptional circumstances such as mismatch between vaccine and circulating virus strains). The population was divided into children, adults and older people, with each group being further subdivided into healthy or at-risk of developing complications of influenza. The three drugs could be used for seasonal or post-exposure prophylaxis, with outbreak control referring to post-exposure prophylaxis in settings where people live or work in close proximity (for example, in residential care). Twenty-two RCTs were identified by the systematic review and a further RCT was provided in a sponsor's submission. No head-to-head RCTs were identified. |
| 4.1.2 | In most RCTs, the effectiveness of antiviral drugs was measured as cases of influenza prevented. These were defined as either cases of symptomatic laboratory-confirmed influenza or clinical illness. The efficacy outcome was presented as the relative risk and protective (or prophylactic or preventive) efficacy of developing influenza with and without prophylaxis. The relative risk is the ratio of the proportion of people developing influenza in the treatment group to the proportion developing influenza in the control group. The lower the relative risk the higher the efficacy of prophylaxis. The protective efficacy is the percentage of people for whom prophylaxis could prevent infection. It is calculated by subtracting the relative risk from 1 (and is expressed as a percentage). |
| 4.1.3 | The background circulating levels of influenza for the duration of the individual RCTs were often not reported clearly. |
| Oseltamivir | |
| 4.1.4 | The Assessment Group's systematic review yielded six RCTs of oseltamivir for prophylaxis. Two RCTs of oseltamivir for seasonal prophylaxis, both included in the previous appraisal, were in healthy adults and one was in older people within a residential care setting. Two studies, one of which was published after and not included in the original review, were of post-exposure prophylaxis in households with mixed adult and child populations. One RCT, published since the previous appraisal, was of oseltamivir for prophylaxis against experimentally induced influenza. A meta-analysis of the two seasonal prophylaxis trials in adults (n=1039) gave a relative risk of developing symptomatic laboratory-confirmed influenza of 0.27 (95% confidence interval [CI] 0.09 to 0.83). The study (n=548) of seasonal prophylaxis in older people showed a 92% protective efficacy for symptomatic laboratory-confirmed influenza (p = 0.002), with an 86% relative reduction in secondary complications. |
| 4.1.5 | The two RCTs (n=1747) of post-exposure prophylaxis in households showed a protective efficacy against symptomatic laboratory-confirmed influenza of 89% (p < 0.001) in one study and 73% in the other. For contacts of influenza-positive index cases (that is people in whom it was confirmed that influenza-like illness was caused by influenza), the protective efficacy was 89% and 68%, respectively. When the results of the two RCTs were pooled by meta-analysis, the resulting relative risk was 0.19 (95% CI 0.08 to 0.45) and the protective efficacy was therefore 81%. For contacts of influenza-positive index cases, relative risk was 0.21 (95% CI 0.08 to 0.58) and the protective efficacy was 79%. Analysis of data limited to children aged 1-12 years from one trial of post-exposure prophylaxis showed a protective efficacy of 64% (relative risk 0.36). The protective efficacy was 55% (relative risk 0.45) for influenza-positive index cases. The trial (n=38) of prophylaxis against experimentally induced influenza B showed a higher rate of infection in the treatment group (relative risk 1.06; 95% CI 0.83 to 1.36). Oseltamivir was of equivalent efficacy in vaccinated and unvaccinated people. |
| Amantadine | |
| 4.1.6 | Eight RCTs were identified by the Assessment Group, none of which were conducted since the previous appraisal. Three trials were of seasonal prophylaxis (two trials in unvaccinated healthy adults and one trial in older people in residential care who were inadequately vaccinated). Two trials investigated outbreak control, one in healthy mostly vaccinated adolescents and one in healthy unvaccinated adults. Three trials were of prophylaxis against experimentally induced influenza in healthy unvaccinated adults. The studies of the efficacy of seasonal prophylaxis were limited by low attack rates. In one study in healthy adults (n=318), the relative risk for clinical symptoms with amantadine prophylaxis was 0.4 (95% CI 0.08 to 2.03). Another study (n=285) in healthy military personnel found no difference in the incidence of acute respiratory illness. |
| 4.1.7 | A study (n=536) of outbreak control in vaccinated adolescent males in a boarding school reported a relative risk of 0.17 (95% CI 0.08 to 0.37) for clinical influenza and a protective efficacy of 90% (95% CI 0.66 to 0.97) for symptomatic laboratory-confirmed influenza. This study also demonstrated that the protective effect of amantadine prophylaxis was limited to the period of prophylaxis. The second study (n=10,053) of outbreak control in unvaccinated adults in semi-isolated engineering schools reported a relative risk for clinical influenza of 0.59 (95% CI 0.49 to 0.70) with amantadine prophylaxis and showed some evidence that prophylaxis reduced the severity and duration of influenza illness. |
| 4.1.8 | The three studies (n=133) of amantadine prophylaxis against experimentally induced influenza showed relative risks of 0.22 for symptomatic laboratory-confirmed influenza, 0.26 and 0.58 for clinical influenza and 0.14 for serologically confirmed influenza. The Assessment Group could not draw firm conclusions about the impact of vaccination status on the efficacy of amantadine prophylaxis. No information was available from the RCTs on the degree of viral resistance. However virological monitoring has documented resistance to amantadine and it is reported that 37% of viral isolates are resistant to amantadine. Development of resistance can occur relatively rapidly during treatment and can lead to the failure of prophylaxis. |
| Zanamivir | |
| 4.1.9 | The Assessment Group's systematic review identified eight RCTs. Four of these, one of seasonal prophylaxis in at-risk adolescent and adults, one of post-exposure prophylaxis in a mixed population and two of outbreak control in at-risk older people in residential care, were new trials not included in the previous appraisal, A. further new RCT, of seasonal prophylaxis in healthcare workers, formed part of the sponsor submission. A trial (n=1107) of zanamivir as seasonal prophylaxis in healthy adults showed a protective efficacy of 68% (95% CI 37 to 83) against symptomatic laboratory-confirmed influenza. The trial was conducted in an influenza season where the vaccine and circulating strain were mismatched. In the unvaccinated subgroup, the protective efficacy was 60% (95% CI 24 to 80). A second study (n=319) of zanamivir for seasonal prophylaxis in healthcare workers showed no statistically significant difference in the development of symptomatic laboratory-confirmed influenza. There was also a study (n=3363) of zanamivir for seasonal prophylaxis in community-dwelling at-risk adolescents and adults (aged 12 years and above). For the intent-to-treat (ITT) population the protective efficacy against symptomatic laboratory-confirmed influenza was 83% and the relative risk was 0.17 (95% CI 0.07 to 0.44). The relative risk did not vary according to vaccination status. The relative risk for developing confirmed influenza with complications was 0.12 (95% CI 0.02 to 0.73). The subgroup of people aged 65 and above, some of whom had further risk factors for influenza complications, showed a relative risk of 0.20 (95% CI 0.02 to 1.72). |
| 4.1.10 | A trial (n=1291) of zanamivir given for 10 days for post-exposure prophylaxis to all household contacts (aged 5 years or older) of a person with an influenza-like illness showed a relative risk for symptomatic laboratory-confirmed influenza of 0.18 (95% CI 0.08 to 0.39). For contacts of influenza-positive index cases the relative risk was 0.20. Another trial (n=837) of 10-day zanamivir for post-exposure prophylaxis in household contacts showed a protective efficacy of 79% (95% CI 62 to 89, relative risk 0.21), and 81% protective efficacy in contacts of influenza-positive index cases (95% CI 62 to 90, relative risk 0.19). Fewer households in the treatment group had contacts who developed complications of laboratory-confirmed influenza (p = 0.01). Two trials (reported jointly, n=288) investigated the use of zanamivir for 5 days for post-exposure prophylaxis in household contacts. The relative risk for developing symptomatic laboratory-confirmed influenza was 0.33 during prophylaxis and the length of illness was shorter in the treatment group (p = 0.016). |
| 4.1.11 | Two studies (n=519) investigated the prevention of influenza outbreaks in older people in long-term residential care. The available data from one of these trials are limited. The second trial was conducted in mostly unvaccinated people and prophylaxis conferred a protective efficacy for symptomatic laboratory-confirmed influenza of 32% during influenza A outbreaks (95% CI 27 to 67). |
| 4.1.12 | Some studies tested the susceptibility of viral isolates to zanamivir and found no evidence of viral resistance. |
| 4.1.13 | Further evidence was submitted by consultees that the incidence of influenza-like illness has been falling consistently over the last 10 years. This has resulted in the lowering of the threshold levels of the surveillance schemes. In addition the influenza season as defined by the surveillance schemes does not exactly correspond to the period during which the virus is circulating in the community as indicated by virological monitoring and virus isolation from clinical specimens. Lastly outbreaks of influenza occur, within localised areas especially in residential care settings, outside of the influenza season. |
| 4.2 | Cost effectiveness |
| 4.2.1 | The Assessment Group identified seven cost-effectiveness studies that included oseltamivir, amantadine or zanamivir for the prophylaxis of influenza, including one sponsor submission from the manufacturer of oseltamivir. No cost-effectiveness analyses were submitted by the manufacturers of amantadine and zanamivir. Two cost-effectiveness studies were UK based and took an NHS perspective (including the assessment for the original appraisal); one was from Canada, one from continental Europe, one from the USA and one from the perspective of the Ministry of Defence in the UK. One study from the UK NHS perspective estimated that the cost-effectiveness of oseltamivir for post-exposure prophylaxis compared with no prophylaxis or treatment was approximately £30,000 per quality-adjusted life year (QALY) gained and compared with no prophylaxis followed by oseltamivir treatment was about £52,000 per QALY gained. The second UK study, the assessment undertaken for the original appraisal, included vaccination as a prophylactic strategy. The model related to seasonal prophylaxis only. All three drug strategies were dominated by vaccination as a prophylactic strategy. When the drugs were combined with vaccination, they were most cost effective for people in residential care, with amantadine in this group having an estimated incremental cost-effectiveness ratio (ICER) per QALY gained of about £29,000 per QALY gained. The cost-effectiveness estimates of amantadine for other groups and oseltamivir and zanamivir for all groups were much higher. |
| 4.2.2 | The submission from the manufacturer of oseltamivir reported a model to estimate the cost effectiveness of oseltamivir for seasonal and post-exposure prophylaxis of influenza, comparing it with amantadine, zanamivir and no prophylaxis for adults and children older than 12 years who were healthy or at-risk, and for children aged 1-12 years and 1-5 years. A cost-effectiveness analysis was undertaken for the comparison of oseltamivir with amantadine or usual care. For the comparison of oseltamivir with zanamivir, it was assumed that both drugs are equally effective and a cost-minimisation analysis was undertaken. The Assessment Group re-analysed the results from the manufacturer's model for oseltamivir to generate full incremental cost-effectiveness estimates (the manufacturer's submission presented pair-wise comparisons rather than a full incremental analysis). Oseltamivir for post-exposure prophylaxis gave ICERs below £8000 per QALY gained for both groups of children, less than £2000 for at-risk adults and about £27,000 for healthy adults. For children in both age groups oseltamivir as seasonal prophylaxis gave ICERs above £46,000 per QALY gained. For healthy or at-risk adults and children (older than 12 years) oseltamivir was dominated by zanamivir, and for the at-risk group the ICERs for amantadine and zanamivir were less than £16,000 per QALY gained. The model was sensitive to the changes in assumptions for attack rates and the number of GP visits per household. |
| 4.2.3 | The Assessment Group conducted an independent economic assessment. The three drugs were cross compared with each other and with no prophylaxis for three age groups: 'children' (aged 1-14 years), 'adults' (aged 15-64 years) and 'older people' (older than 65 years). Each age group was subdivided into healthy and at-risk, and each of these six subgroups was further divided on the basis of vaccination status. Because all the costs and benefits occurred within a single influenza season, the time horizon was 1 year and therefore there was no discounting, except for life years lost because of premature death caused by influenza and its complications. The model considered the costs and outcomes of influenza-like illness. The probability that a contact develops influenza depends on the influenza attack rate, the prophylactic efficacy of the intervention strategy and the person's vaccination status. For amantadine it also depends on the probability that influenza is of type A and the degree of resistance of the virus to the drug. Contacts who develop influenza may seek medical treatment and receive treatment with oseltamivir and zanamivir if at risk, in line with 'Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza' (NICE technology appraisal guidance 58). People who develop complications seek medical attention and receive antibiotics. A proportion are hospitalised and some may die. |
| 4.2.4 | The model assumed prophylaxis is effective only for the period the person is taking the drug. It also assumed that the benefits of vaccination and prophylaxis are cumulative, and that prophylaxis would only be considered when it is known that influenza is circulating in the community above a threshold of 30 new GP consultations for influenza-like illness per week per 100,000 population. The model did not consider the benefits of prophylaxis in preventing transmission of influenza from the person who receives prophylaxis and avoids infection, to others who may have contracted the illness from this person. |
| 4.2.5 | The baseline influenza attack rate is the probability that an individual develops influenza over the influenza season. The model assumed this differs in each age group and within the models for seasonal and post-exposure prophylaxis. For seasonal prophylaxis in children it was 0.174, adults 0.062 and older people 0.052. For post-exposure prophylaxis in children it was 0.189, for adults 0.088 and for older people 0.088. The probability that influenza-like illness is true influenza was derived from Royal College of General Practitioners' data. This was estimated to be 0.5 across all subgroups for the duration when influenza is circulating in the community above the threshold of 30 new GP consultations for influenza-like illness per week per 100,000 population. This figure was used together with the true influenza attack rate to calculate the influenza-like illness attack rate. |
| 4.2.6 | The probability influenza is influenza A was based on virological surveillance data for 12 influenza seasons (1995-6 to 2006-7). The probability that influenza A was the dominant strain in a given season was calculated at 0.75. The probability that a case was influenza A was calculated separately for years where influenza A was dominant (0.86) and for years where influenza B was dominant (0.30). The overall mean probability that a case of influenza is influenza A was estimated to be 0.72. |
| 4.2.7 | The duration of the influenza season was calculated as the period for which the number of new GP consultations for influenza-like illness per week was above the threshold level of 30 (previously 50) per 100,000 population for the past 20 influenza seasons (1987-8 to 2006-7).The mean duration of the influenza season was calculated to be 5.71 weeks. It was assumed that vaccination is effective over the whole of the season but that drugs are effective only for the time they are taken. Hence the preventive efficacy of antivirals was adjusted according to the proportion of the influenza season for which the drugs were taken. |
| 4.2.8 | The protective efficacies of vaccination, amantadine, oseltamivir and zanamivir were derived from the review of clinical effectiveness (and Cochrane reviews for vaccination). The relative risks for vaccination were 0.36 for healthy children, 0.35 for healthy adults and 0.42 in older people. The model assumed that people who stopped prophylaxis did so at the beginning of the course and received no protective benefit. The protective efficacy of vaccination reduced the probability of developing influenza without prophylaxis in the model. The joint benefit of vaccination and prophylaxis was assumed to be cumulative - that is, the effectiveness of prophylaxis was applied to only that proportion of the vaccinated population who were not effectively protected by vaccination. |
| 4.2.9 | There was a lack of clinical effectiveness evidence for a number of subgroups in the cost-effectiveness analysis. Because of the lack of evidence the relative risk for seasonal prophylaxis with amantadine was taken from a study of unvaccinated healthy adults and applied to all population subgroups. For post-exposure prophylaxis with amantadine, efficacy was taken from a single study of outbreak control in vaccinated healthy adolescents and applied to all groups in the model. The model also assumed, based on data from the 2006-7 season, that in 37% of influenza cases people were resistant to amantadine. For seasonal prophylaxis with oseltamivir the results of the study in healthy unvaccinated adults were applied to healthy and at-risk adults and children, and the results of the trial in at-risk people in residential care were applied to healthy and at-risk older people. For post-exposure prophylaxis with oseltamivir, a meta-analysis was performed of two trials from healthy adults and the results applied to the healthy and at-risk adult and older subgroups and the results of the subgroup analysis for children in these trials were applied to the healthy and at-risk child subgroups. For seasonal prophylaxis, a trial in healthy and mostly unvaccinated adults was used to calculate the relative risk for the healthy adults and the at-risk and healthy child groups. A study of seasonal prophylaxis in at-risk adults supplied estimates for the at-risk adult and the older populations. For post-exposure prophylaxis with zanamivir a meta-analysis of three trials in adults and children was conducted and the results applied to all population groups. |
| 4.2.10 | The model included the probability of adverse effects from vaccination and amantadine only and the resulting costs and health effects. Adverse effects from oseltamivir and zanamivir were assumed to be mild and self-limiting and not to have an impact on a person's health-related quality of life. The model also assumed a withdrawal rate from amantadine prophylaxis of 5.7% in children and healthy adults and 14.7% in at-risk adults and older people, and withdrawal from oseltamivir and zanamivir of 1.3% for all model subgroups. |
| 4.2.11 | Not all people with influenza-like illness (who are at risk) were assumed to be treated. The model estimated the probability that a person with influenza-like illness presents to a medical practitioner, the probability this is within 48 hours and the probability of treatment being prescribed. Eighty-nine percent of treatments with a neuraminidase inhibitor were assumed to be with oseltamivir and 11% with zanamivir in line with market research. |
| 4.2.12 | The relative risk for complications following treatment was the same as that used in 'Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza' (NICE technology appraisal guidance 67). The model also included the probability of developing complications from influenza or influenza-like illness, the probability of receiving antibiotics, the probability of hospitalisation because of a complication (including intensive care treatment) and the probability of death because of a complication related to an influenza-like illness. |
| 4.2.13 | The model operates in terms of QALYs lost over the influenza season. The difference in QALYs lost between prophylactic options is the estimate of QALYs saved. QALYs are lost for adverse effects, episodes of influenza and influenza-like illness, complications of influenza and influenza-like illness and premature death as a result of complications. Estimates of health-related quality of life were obtained from oseltamivir studies. The method for obtaining utility values used in the model was non-reference case, derived from measures on a 10-point scale from the oseltamivir trials. The adverse effects of amantadine were assumed to cause a 0.2 utility decrement for a mean duration of 5 days. Health utility decrements associated with complications of influenza-like illness were derived from a study that used committee consensus to reach estimates and were assumed to operate for the duration of complications in clinical trials for oseltamivir. |
| 4.2.14 | The model included costs for acquisition and administration of vaccination and antiviral prophylaxis and treatment, costs associated with the management of adverse effects, consultation costs, antibiotics and costs of hospitalisation, including intensive care. The model assumed that each prescription of prophylaxis requires a GP consultation but explored the possibility of prescribing multiple courses of prophylaxis (for example, for family contacts) at a single visit. |
| 4.2.15 | Sensitivity analyses were carried out using the new lower price for zanamivir, which the manufacturer informed NICE had been approved by the Department of Health. The effect of multiple prescriptions per GP consultation was examined. Seasonal prophylaxis would be considered in the exceptional event of a mismatch between circulating and vaccine virus strains. In such a situation the protective efficacy of vaccination would decrease, the extent of such a decrease being determined by the degree of mismatch. This was explored by analyses in which the relative risk for vaccination was 0.5 or 0.75. Because the trials for oseltamivir and zanamivir occurred in different settings with differing circulating levels of influenza, virus strains and populations, the differing estimates of efficacy are not strictly comparable. To explore the impact of this an analysis was conducted in which both drugs were considered to be of equal efficacy. Further analyses exploring the effect of assuming resistance to oseltamivir and varying the influenza attack rates were also conducted. |
| 4.2.16 | The model gave the following results for seasonal prophylaxis. In healthy children, oseltamivir economically dominated amantadine and zanamivir. That is, treatment with oseltamivir was expected to cost less and result in more QALYs gained. For unvaccinated children the ICER was £44,007 per QALY gained and for vaccinated children it was £129,357 per QALY gained. For at-risk children oseltamivir dominated the other drugs, with an ICER of £16,630 per QALY gained for unvaccinated children and £51,069 per QALY gained for vaccinated children. In healthy adults oseltamivir dominated the other drugs, with ICERs of £147,505 in unvaccinated adults and £427,184 in vaccinated adults. For at-risk adults oseltamivir again dominated the other drugs, with ICERs of £63,552 in unvaccinated people and £186,651 in vaccinated people. For healthy older people oseltamivir dominated the other drugs, with ICERs of £49,742 in unvaccinated people and £121,728 in vaccinated people. In at-risk older people oseltamivir dominated the other drugs, with ICERs of £38,098 per QALY gained for unvaccinated people and £93,763 for vaccinated people. |
| 4.2.17 | For post-exposure prophylaxis in healthy children zanamivir economically dominated oseltamivir and amantadine, with ICERs of £23,225 per QALY gained in unvaccinated children and £71,648 per QALY gained in vaccinated children. For post-exposure prophylaxis in at-risk children zanamivir dominated the other drugs, with ICERs of £8233 for unvaccinated children and £27,684 for vaccinated children. For post-exposure prophylaxis in healthy adults oseltamivir dominated zanamivir and amantadine, with ICERs of £34,181 for unvaccinated people and £103,706 for vaccinated people. For post-exposure prophylaxis in at-risk adults oseltamivir dominated the other drugs, with ICERs of £13,459 per QALY gained for unvaccinated adults and £43,970 for vaccinated adults. In healthy older people oseltamivir dominated zanamivir and amantadine, with an ICER of £10,716 per QALY gained for unvaccinated people and £28,473 for vaccinated people. For post-exposure prophylaxis in at-risk older people oseltamivir again dominated, with ICERs of £7866 for unvaccinated people and £21,608 for vaccinated people. |
| 4.2.18 | When the lower price of zanamivir was used in the economic model it had little impact on the outcome of the comparisons made in the base case for seasonal prophylaxis except for at-risk adults. In this group zanamivir was no longer dominated; the ICER was £53,159 per QALY gained. For post-exposure prophylaxis the price reduction led to improvements in the cost effectiveness of zanamivir for healthy and at-risk children. In general, the estimates for cost effectiveness were sensitive to the influenza attack rates, the level of viral resistance, vaccine efficacy, the threshold used to describe when influenza is circulating in the community, the relative efficacy of oseltamivir and zanamivir and the risk of hospitalisation in people without complications. For seasonal prophylaxis, the estimates were sensitive to the discount rate and for post-exposure prophylaxis they were sensitive to the use of multiple prescriptions for prophylaxis per GP visit. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of oseltamivir, amantadine and zanamivir, having considered evidence on the nature of the condition and the value placed on the benefits of oseltamivir, amantadine and zanamivir by people with exposure to influenza-like illness, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. |
| 4.3.2 | The Committee accepted that there was evidence from RCTs that the neuraminidase inhibitors were effective at preventing laboratory-proven influenza infection. It understood that influenza causes a wide spectrum of respiratory illness of varying severity, and could lead to a number of potentially important complications especially in certain at-risk groups. The Committee discussed the definition of at-risk groups for prophylaxis and decided that they would be best defined in the same way as for the current recommendations for vaccination. From the outset the Committee was of the view that vaccination has appropriately been established as the first-line intervention to prevent influenza and its complications, and was mindful that the use of drug prophylaxis should not in any way detract from efforts to ensure that all eligible people are vaccinated at the beginning of each influenza season. However, the Committee also accepted that because of the antigenic variation in circulating influenza viruses, vaccination may not always be fully effective in a particular season and thus a mismatch between vaccine and circulating virus strains could result in vaccination conferring significantly lower protection than predicted. |
| 4.3.3 | The Committee accepted that as prophylaxis is used when the person is exposed to a person with clinically defined influenza-like illness and not confirmed influenza, a crucial factor in the effectiveness and cost effectiveness would be the probability that a case of influenza-like illness was true influenza. The Committee agreed that this probability would be highest when the virus was known to be circulating in the community. The Committee agreed that the circulating level of influenza virus would determine attack rates and was aware that the values used in the economic analysis, which were derived from intensively monitored clinical trials, were possibly higher than those that would routinely occur in normal clinical situations. |
| 4.3.4 | The Committee noted that the threshold levels used to determine whether influenza virus was circulating in the community (as recommended by the Health Protection Agency) were based on clinical consultations and did not always coincide with timing of the emergence of virological evidence. The Committee heard from clinical experts that the threshold levels were an artificial construct that may not be suitable for defining when the use of drug prophylaxis would be most efficacious because they were not created for this purpose. The Committee was aware of the need for a method that could routinely be used to identify periods of circulation of influenza viruses in order to determine when influenza prophylaxis should be recommended but was not presented with any alternative to threshold levels. The Committee accepted that virological testing was possible and that results could be available within 24-48 hours. However, the Committee recognised that to do so routinely in individual cases may be impractical. In addition the Committee was aware that any delay caused by awaiting results of virology tests would have implication for the timing of the use of prophylaxis with respect to the exposure and alter the efficacy of prophylaxis. The Committee was also aware that outbreaks of influenza were common within localised environments, such as residential care establishments, outside the influenza season as defined by the thresholds and that unless such outbreaks could be identified, it would not be possible to establish situations in which use of prophylaxis would be cost effective. |
| 4.3.5 | The Committee considered the evidence for effectiveness of the individual drugs and the emergence of additional evidence since the publication of 'Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza' (NICE technology appraisal guidance 67). The Committee accepted that the drugs were clinically effective when used as seasonal or post-exposure prophylaxis. It noted that there were no head-to-head trials of the interventions and because the individual trials were conducted in differing populations, the results may not reflect accurately any differences in efficacy between the drugs. In addition, the Committee noted that the relative risks used in the economic modelling needed to be extrapolated to many groups in which there were no trials, from other groups in which there were trial data. Therefore the Committee agreed that it would need to be cautious in appraising the results of the economic analysis for groups for which the suggestion of underlying differences in efficacy between the drugs was based on assumptions and not trial evidence. |
| 4.3.6 | The Committee accepted that the neuraminidase inhibitors were generally safe and well tolerated. It was aware of concerns that have been raised with regulatory authorities in Canada, Japan and the USA about possible neuropsychiatric events associated with oseltamivir in adolescents, but that no specific guidance regarding safety has been issued by the European Medicines Agency or the Medicines and Healthcare products Regulatory Agency. The Committee accepted that amantadine was associated with more frequent adverse effects. The Committee also accepted evidence of viral resistance to amantadine and noted that although currently low there was evidence of increasing resistance to the neuraminidase inhibitors. |
| 4.3.7 | The Committee considered the consequences of developing influenza and the costs and outcomes of these used in the economic model. It was aware of clinical expert opinion that there was no evidence that the use of prophylaxis decreased hospitalisations associated with influenza-like illness as included in the model. However, the Committee accepted that preventing an influenza infection could logically and plausibly be expected to result in a decrease in the adverse consequences of the illness. |
| 4.3.8 | The Committee considered the cost effectiveness of the use of seasonal prophylaxis. In doing so it was aware that clinical expert opinion did not favour the use of drug prophylaxis in this manner. The Committee also noted that because seasonal prophylaxis would be considered only in exceptional situations such as a mismatch between vaccine and circulating virus, the efficacy of vaccination assumed should be intermediate between the extremes of the values used for unvaccinated and vaccinated relative risks in the model. The Committee agreed that the ICERs for the various subgroups examined in the modelling suggested that overall seasonal prophylaxis was not a cost-effective use of NHS resources. The Committee specifically noted that the modelled ICER for seasonal prophylaxis in unvaccinated at-risk children was approximately £16,600 per QALY gained. However, this ICER was very sensitive to the assumption of the attack rate and the Committee was persuaded that, because of the uncertainties regarding the clinical effectiveness data to support this value, it may have been overestimated in the model. In addition, the relative risk for this subgroup of children had been extrapolated from a trial in healthy adults and was not based on direct empirical evidence. Therefore the Committee agreed that it would not recommend seasonal prophylaxis with oseltamivir, amantadine or zanamivir. |
| 4.3.9 | The Committee considered the results of the economic evaluation for the use of the drugs for post-exposure prophylaxis. The Committee noted that the ICERs for thevarious subgroups would indicate that the use of post-exposure prophylaxis was cost effective in at-risk groups only who had either not been vaccinated or not been adequately protected by vaccination. The ICERs in these subgroups ranged from £7866 per QALY gained for unvaccinated at-risk older people, to £8233 per QALY gained for unvaccinated at-risk children and £13,459 per QALY gained for unvaccinated at-risk adults. This would include people in whom vaccination was contraindicated and when the vaccine and circulating strains of virus were sufficiently different to mean that vaccination did not provide adequate protection. The Committee was aware that the cost effectiveness depended on the probability that influenza-like illness in the index case was influenza. It also noted that the contact with the index case would need to be of a sufficiently intense degree, such as that experienced by living together. The Committee concluded that post-exposure prophylaxis was a cost-effective use of resources for at-risk persons who were not adequately protected by vaccination, but only when it has been established that influenza is circulating in the community. |
| 4.3.10 | The Committee then discussed which, if any, of the two neuraminidase inhibitors should be prescribed if post-exposure prophylaxis were considered appropriate in the subgroups identified. The Committee was aware of the limitations in the evidence base for comparative efficacy of the two drugs and it was not persuaded that there was evidence of differential effectiveness between the two drugs. However, the Committee noted that the drugs were administered differently and that zanamivir was not licensed for children under 5. The Committee accepted that if the two drugs were considered of equal effectiveness the economic analysis indicated that the less costly drug would be more cost effective. The Committee concluded that it was not possible to give specific recommendations for one or other of the neuraminidase inhibitors, and therefore the decision on which to prescribe should be determined by the healthcare professional in consultation with patients and carers on a case-by-case basis, taking into account preferences regarding the delivery of the drug and potential adverse effects and contraindications. If all other considerations are equal, the choice should be based on the least costly option within the marketing authorisations of the products. |
| 4.3.11 | The Committee carefully considered the need for managing outbreaks that occurred outside the influenza season defined by the surveillance threshold. It noted that such outbreaks often occurred in residential care establishments and were frequently associated with poor outcomes and complications in vulnerable populations. However, the Committee agreed that, because the neuraminidase inhibitors are only effective against true influenza, the cost-effectiveness of the use of prophylaxis in such situations would still depend on the probability that the influenza-like illness was influenza. The Committee was persuaded that this probability was low in the absence of wider circulation of influenza. Therefore the Committee agreed that in such situations there would need to be firmer evidence that the influenza-like illness was influenza. Such evidence could be supplied by virological testing to establish influenza positivity. The Committee noted that the population in residential care were most likely to be older people or people otherwise at risk of influenza complications. For this subgroup the use of post-exposure prophylaxis gave, for the most part, acceptable ICER estimates from the economic model for both the vaccinated and unvaccinated subgroups. In addition the Committee was aware that in the event of an influenza outbreak within a residential setting, the attack rates were likely to be higher than those used in the model for post-exposure prophylaxis, which would result in improved cost effectiveness of the prophylactic intervention. Therefore the Committee recommended that when surveillance schemes do not indicate that influenza virus is at the level of 'normal seasonal activity' (i.e. out of season), oseltamivir and zanamivir may still used as options for post-exposure prophylaxis in vaccinated or unvaccinated individuals living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence, of infection with influenza in the incident case or cases. |
| 4.3.12 | The Committee noted that there was no new evidence for the efficacy of amantadine in various subgroups since the publication of 'Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza' (NICE technology appraisal guidance 67). In addition, a high incidence of viral resistance to amantadine has developed and, compared with the neuraminidase inhibitors, amantadine is associated with a greater incidence of adverse effects. The Committee noted that the economic analysis did not indicate that amantadine would be a cost-effective use of resources in any subgroup for any indication. Therefore the Committee did not recommend amantadine for prophylaxis of influenza. |
| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 |
NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]
|
| 6 | Proposed recommendations for further research |
| 6.1 | None identified. |
| 7 | Related NICE guidance |
|
Published
|
| 8 | Proposed date for review of guidance |
| 8.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 8.2 | It is proposed that the guidance on this technology is considered for review in 2011. The guidance can be routinely reviewed in 3 years because no changes in the evidence are expected before then. The Institute would particularly welcome comment on this proposed date. |
David Barnett
Chair, Appraisal Committee
May 2008
| Appendix A. Appraisal Committee members and NICE project team |
| Appraisal Committee members |
|
The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice-chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches. Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. Dr Jane Adam Professor AE Ades Dr Amanda Adler Dr Tom Aslan Professor David Barnett (Chair) Mrs Elizabeth Brain Professor Karl Claxton Dr Richard Cookson Simon Dixon Mrs Fiona Duncan Professor Christopher Eccleston Dr Paul Ewings Professor John Geddes Mr John Goulston Mr Adrian Griffin Dr Rowan Hillson Professor Philip Home (Vice Chair) Dr Terry John Dr Vincent Kirkbride Dr Simon Maxwell Dr Alec Miners Mrs Angela Schofield Dr Joe Silas Mr Mike Spencer Mr David Thomson Dr Norman Vetter Dr Paul Watson |
| NICE project team |
|
Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager. Elangovan Gajraj Helen Chung Eloise Saile |
| Appendix B. Sources of evidence considered by the Committee | |
| A |
The assessment report for this appraisal was prepared by ScHARR, University of Sheffield.
|
| B | The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I and II were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination. |
| I |
Manufacturers/sponsors:
|
| II |
Professional/specialist and patient/carer groups:
|
| III |
Other consultees
|
| IV |
Commentator organisations (did not provide written evidence and without the right of appeal)
|
| C |
The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on oseltamivir, amantadine and zanamivir by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.
|
This page was last updated: 30 March 2010