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CLINICAL & COST- EFFECTIVENESS OF NEURAMINIDASE INHIBITORS FOR THE TREATMENT & PREVENTION OF INFLUENZA Nicola Cooper, PhD & Alex Sutton, PhD Centre for.

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Presentation on theme: "CLINICAL & COST- EFFECTIVENESS OF NEURAMINIDASE INHIBITORS FOR THE TREATMENT & PREVENTION OF INFLUENZA Nicola Cooper, PhD & Alex Sutton, PhD Centre for."— Presentation transcript:

1 CLINICAL & COST- EFFECTIVENESS OF NEURAMINIDASE INHIBITORS FOR THE TREATMENT & PREVENTION OF INFLUENZA Nicola Cooper, PhD & Alex Sutton, PhD Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, University of Leicester, UK. Clinical Trials Research Unit, University of Auckland, December 2003

2 ACKNOWLEDGEMENTS DAVID TURNER, Research Associate in Health Economics, Trent Institute for Health Services Research, University of Leicester, UK ALLAN WAILOO, Lecturer in Health Economics, Sheffield Health Economics Group, ScHARR, University of Sheffield, UK KARL NICHOLSON, Professor of Infectious Diseases, Department of Infection Immunity and Inflammation, University of Leicester, UK KEITH ABRAMS, Professor of Medical Statistics, Centre for Biostatistics & Genetic Epidemiology, University of Leicester, UK

3 OBJECTIVE To establish the clinical & cost- effectiveness of zanamivir & oseltamivir for the treatment & prevention of influenza A & B to provide guidance to the NHS in England & Wales Research commissioned by NHS Research & Development Health Technology Assessment Programme in UK on behalf of National Institute of Clinical Excellence (NICE)

4 BACKGROUND INFLUENZA: –For most individuals, flu is a self- limiting illness with most symptoms clearing after about a week. –BUT flu can cause serious complications & in some cases death, mostly for those considered at high risk (e.g. over 65 years &/or with chronic conditions) –Inflicts considerable costs on the economy through lost work days

5 BACKGROUND (cont.) POLICY IN UK PRIOR TO ASSESSMENT: For prevention: –Recommends vaccination of all high-risk individuals including those aged over 65 years &/or with concomitant disease (e.g. chronic respiratory disease, diabetes or significant cardiovascular disease) For treatment: –Recommends use of zanamivir to treat high-risk adults when flu is circulating in the community. –Recommends otherwise healthy individuals to stay at home & take medicines from the chemist (pharmacist) to relieve the symptoms.

6 BACKGROUND (cont.) NEURAMINIDASE INHIBITORS “ represent a rational approach to flu management to complement vaccination, particularly in ‘high risk’ individuals.” OSELTAMIVIR (Tamiflu, Roche): Licensed in UK for treatment of flu A & B for adults & children over one year of age ( within 48 hours of onset ) & for prevention in adolescents & adults. Administered orally. ZANAMIVIR (Relenza, GlaxoSmithKline): Licensed in UK for treatment of flu A & B for persons aged 12 years & above ( within 48 hours of onset ). Not licensed for prevention. Administered via a Diskhaler TM.

7 OUTLINE PART A : Systematic review & meta-analyses of the effectiveness of NIs for the treatment & prevention of influenza PART B : Cost-effectiveness of NIs for the treatment & prevention of influenza

8 SYSTEMATIC REVIEW & META- ANALYSES OF EFFECTIVENESS OF NIs FOR TREATMENT & PREVENTION OF INFLUENZA

9 METHODS OBJECTIVE : To review clinical effectiveness of NIs for treatment & prevention of influenza A & B. DATA SOURCES : Published studies retrieved from electronic databases with supplementary data obtained from manufacturers SELECTION : Randomised controlled, double blind trials that met following criteria –Published in English –Data available before 31 st Dec 2001 –Evaluated treatment or prevention of naturally occurring flu with zanamivir or oseltamivir (using formulation & dosage licensed for clinical use)

10 METHODS (cont.) POPULATION GROUPS: –Otherwise healthy adults aged 12 to 64 years –Children aged 12 years and under –‘High risk’ individuals; that is, aged 65 years and above, and/or with certain chronic medical conditions (e.g. chronic respiratory disease, diabetes or significant cardiovascular disease) Intention-to-treat (i.e. all individuals in trial) & Influenza positive (i.e. subgroup of individuals with laboratory confirmed flu only) NOTE: Where trials reported combined results for, say, ‘otherwise healthy’ & ‘high risk’ individuals, the required data split by population group were requested from the drug companies.

11 TREATMENT

12 TREATMENT: Primary Endpoints Median time to alleviation of symptoms –Measured in ½ days for zanamivir & hours for oseltamivir

13 TREATMENT: Systematic review

14 TREATMENT: Zanamivir

15 TREATMENT: Zanamivir (ITT) Median time to symptoms alleviated

16 TREATMENT: Zanamivir (FLU +ve) Median time to symptoms alleviated

17 TREATMENT: Zanamivir COMPLICATIONS REQUIRING ANTIBIOTICS -Limited trial level evidence obtainable from published literature -Two published pooled meta-analyses: Monto et al 1999 reported 29% (10% to 44%) relative reduction (zanamivir vs. placebo) in odds of complications requiring antibioitcs in ITT population (all 3 population groups combined) Lalezari et al 2001 reported 43% (-3% to 69%) relative reduction (zanamivir vs. placebo) in odds of complications requiring antibiotics in ‘high risk’ flu positive population

18 TREATMENT: Zanamivir Median time to return to normal activities Otherwise healthy adults ITT: -0.5 days (-1.0 to 0.0) Flu +ve:-0.5 days (-0.9 to 0.0) High risk ITT:-0.1 days (-1.0 to 0.8) Flu +ve:-0.2 days (-1.2 to 0.8) Children ITT:-0.5 days (-1.2 to 0.2) Flu +ve:-0.5 days (-1.3 to 0.3)

19 TREATMENT: Oseltamivir

20 TREATMENT: Oseltamivir (ITT) Median Time to symptoms alleviated

21 TREATMENT: Oseltamivir (FLU +ve) Median Time to symptoms alleviated

22 TREATMENT: Oseltamivir COMPLICATIONS REQUIRING ANTIBIOTICS -Limited trial level evidence obtainable from published literature -One published pooled meta-analyses: -Kaiser et al 2003 reported 68% (41% to 84%) relative reduction (zanamivir vs. placebo) in odds of lower respiratory tract complications in ‘otherwise healthy’ flu positive population & 38% (6% to 60%) in ‘high risk’ flu positive population

23 TREATMENT: Oseltamivir Median time to return to normal activities: Measured on an 11-point visual analogue scale (0 unable to perform normal activity, 10 fully able to perform normal activity) Otherwise healthy adults ITT: -1.3 days (-1.9 to -0.7) Flu +ve:-1.6 days (-2.6 to -0.7) High risk ITT:-2.5 days (-4.9 to -0.0) Flu +ve:-3.0 days (-5.9 to –0.1) Children ITT:-1.3 days (-1.8 to -0.7) Flu +ve:-1.9 days (-2.7 to -1.1)

24 TREATMENT: Summary Treating ‘otherwise healthy’ adults and children with zanamivir & oseltamivir REDUCES duration of symptoms in ITT population by between 0.4 and 1.0 day when taken within 48 hours. Results less conclusive for ‘high risk’ group in ITT population BUT based on fewer individuals CAUTION required when comparing zanamivir & oseltamivir directly because definition of symptoms alleviated different ( NO HEAD-TO-HEAD TRIALS ) Proportion of flu positive individuals in trials (  49%) may be higher than in clinical practice => treatment effects may not be achievable in routine practice

25 TREATMENT: Summary (cont.) Data on complications relied on pooled marginal meta-analysis & thus did NOT take into account any heterogeneity between trials Unclear how well complications requiring antibiotics correlate with incidence of more serious complications requiring admission to hospital or causing death (NO deaths in trials). Trials underpowered in terms of complication outcomes Reduction in median time to return to normal activities between 0 and 3 days depending on drug and population group

26 PREVENTION

27 PREVENTION: Primary Endpoints Number of laboratory confirmed symptomatic flu episodes avoided Four different preventative strategies for administering NIs evaluated in literature: 1)Outbreak prophylaxis in elderly at residential home setting 2)Seasonal prophylaxis in elderly at residential home setting 3)Seasonal prophylaxis in health population 4)Post-exposure prophylaxis in household setting

28 PREVENTION: Systematic review

29 PREVENTION: Zanamivir

30 Seasonal prophylaxis in otherwise healthy population – 39% (36% to 86%) relative reduction (zanamivir vs. placebo) in the odds of developing flu Post-exposure prophylaxis in household setting – 81% (62% to 91%) relative reduction(zanamivir vs. placebo) in the odds of developing flu

31 PREVENTION: Oseltamivir

32 Seasonal prophylaxis in elderly residential home setting – 92% (39% to 99%) relative reduction (oseltamivir vs. placebo) in odds of developing flu Seasonal prophylaxis in otherwise healthy population – 74% (16% to 92%) relative reduction in odds of developing flu Post-exposure prophylaxis in household setting – 90% (71% to 96%) relative reduction in odds of developing flu

33 PREVENTION: Summary NIs given for preventing flu led to a relative reduction of 70% to 90% in odds of developing flu, depending on strategy adopted & population studied Lack of evidence for use of NIs for preventing flu in children and in frail elderly individuals in residential care

34 FURTHER ISSUES For economic model need MEAN time to alleviation of symptoms and MEAN time to return to normal activities. Undefined if the last observation is censored.

35 Often only median time to an event reported. BUT for economic evaluation need mean time From median only – a exponential distribution can be assumed to estimate the mean FURTHER ISSUES Mean = 1/ Var = 1/ 2

36 FURTHER ISSUES From survival curve may be possible to derive individual patient data (IPD) & extrapolate using Exponential or Weibull distribution

37 COST-EFFECTIVENESS OF NEURAMINIDASE INHIBITORS FOR THE TREATMENT & PREVENTION OF INFLUENZA

38 METHODS DESIGN: Cost-effectiveness analysis using a probabilistic decision tree model OUTCOME: Cost per Symptom Day Avoided & Cost per Quality Adjusted Life Year (QALY) DATA: For effectiveness & QALYs data obtained from RCTs. Supplementary data obtained from literature using best available evidence. POPULATION GROUPS: ‘Otherwise healthy’ adults, children & ‘high risk’ individuals

39 METHODS: Decision model Decision tree model constructed to compare costs & benefits generated by offering flu treatments to individuals with INFLUENZA LIKE ILLNESS (ILI) with current practice (i.e. no treatment) Probabilistic analysis of decision model using Monte Carlo simulation – i.e. all model parameters were specified with uncertainty in the form of a distribution Model fitted & evaluated in DATA Treeage Professional Economic evaluation from health service perspective

40 TREATMENT

41 TREATMENT: Drug Costs Zanamivir: Dry powder for inhalation disks containing 4 blisters of zanamivir 5mg/blister, net price 5 disks with Diskhaler® device = £ mg twice daily for 5 days = £24.00+VAT Oseltamivir: Capsules, grey/yellow, oseltamivir (as phosphate) 75 mg, net price 10-cap pack = £ mg twice daily for 5 days = £18.18+VAT (NOTE: £1 = 2.65NZ$)

42 TREATMENT: Model Structure Decision to consult health care provider Outcome of illness The policy decision Does the individual have influenza Treatment options No antiviral treatment available NIs available Zanamivir available Oseltamvir available ILI is not influenza ILI is influenza Individual has an ILI Does individual present to health care provider Does not present Presents before 48 hours Presents after 48 hours Individuals with ILI Recovers with no need of further treatment Complication requiring revisit to GP Hospitalisation Death Health care provider prescribes an antiviral Yes/No Oseltamvir available

43 TREATMENT: Model Structure Recover

44 TREATMENT: Model Structure

45 TREATMENT: Different Models BASE-CASE MODEL – considers effect that successful treatment has on quality of life derived from avoiding days of illness due to flu. EXTRAPOLATED MODEL – expands base-case model to consider effects that successful treatment could have on avoiding complications of flu & benefits of successful treatment in terms of avoided hospitalisations & mortality. No direct evidence available, therefore used reduction in pneumonia due to use of NIs (extracted from trials) to predict likely effect on other serious complications that would lead to hospitalisations or death

46 TREATMENT: Healthy Adults Base-Case Results Extrapolated Results

47 TREATMENT: Healthy Adults UK£ NZ$ Willingness to pay for additional QALY (£’000s)

48 TREATMENT: High Risk Base-Case Results Extrapolated Results

49 TREATMENT: High Risk UK£ NZ$ Willingness to pay for additional QALY (£’000s)

50 TREATMENT: Children Base-Case Results Extrapolated Results

51 TREATMENT: Children UK£ NZ$ Willingness to pay for additional QALY (£’000s)

52 TREATMENT: Sensitivity Analysis Identification of most influential parameters Probability of presenting to GP if NIs available Probability individuals presenting to GP with ILI are influenza positive Probability individuals present to GP within 48 hours of first symptoms of flu

53 TREATMENT: Sensitivity Analysis Otherwise Healthy Adults (similar results for other population groups) (i.e. diagnostic accuracy)

54 TREATMENT: Sensitivity Analysis Otherwise Healthy Adults (Assumed NIs ineffective if given after 48 hours)

55 TREATMENT: Sensitivity Analysis Otherwise Healthy Adults

56 TREATMENT: Summary Treatment of flu base-case models indicate relatively favourable cost-effectiveness ratios for all three population groups (i.e. prob(CE)>0.5 at £30,000 per additional QALY). If NIs reduce hospitalisations & deaths caused by flu, as assumed in extrapolated model, then NIs may be highly cost-effective treatment. However, more evidence is needed

57 TREATMENT: Summary BUT, these results need to be interpreted with CAUTION due to sensitivity of results to: Diagnostic certainty (may be improved by development of rapid diagnostic tests) Changes in propensity to consult with a GP caused by availability of NIs (possibility NIs prescribed by nurses or pharmacists) Number of individuals presenting after 48 hours who receive NI ineffectively All of the above factors need to be taken into account if prescribing of NIs is to be cost- effective

58 PREVENTION

59 PREVENTION: Drug Costs Zanamivir: Dry powder for inhalation disks containing 4 blisters of zanamivir 5mg/blister, net price 5 disks with Diskhaler® device = £ mg once daily for 6 weeks = £100.8+VAT Oseltamivir: Capsules, grey/yellow, oseltamivir (as phosphate) 75 mg, net price 10-cap pack = £ mg once daily for 6 weeks = £76.36+VAT (NOTE: £1 = 2.65NZ$)

60 DECISION MODEL: Prevention Seasonal Prophylaxis Strategy (SPS)

61 PREVENTION (SPS): Healthy Adults

62 PREVENTION (SPS): High Risk

63 PREVENTION (SPS): Children

64 DECISION MODEL: Prevention Post-Exposure Prophylaxis Strategy (PEP) (Note: only oseltamivir considered as zanamivir not licensed)

65 PREVENTION (PEP)

66 PREVENTION (PEP): Healthy Adults Otherwise healthy unvaccinated adults 0 54, , , , ,000 UK£ NZ$ Willingness to pay for additional QALY

67 PREVENTION (PEP): High Risk High-risk unvaccinated adults 0 54,000108, , , ,000 UK£ NZ$ Willingness to pay for additional QALY

68 PREVENTION (PEP): High Risk High-risk vaccinated adults Willingness to pay for additional QALY 0 54, , , , ,000 UK£ NZ$

69 PREVENTION (PEP): Sensitivity (i.e. probability that an individual exposed to someone with ILI develops influenza)

70 PREVENTION: Summary SEASONAL PROPHYLAXIS : For all population groups, NI strategies (oseltamivir & zanamivir) dominated by vaccination when compared to no intervention (i.e. more costly & less effective) –Largely due to fact that NIs only protective whilst being taken. POST-EXPOSURE PROPHYLAXIS : –For otherwise healthy or high risk vaccinated adults, oseltamivir cost-ineffective. [prob(CE)<0.5 at £30,000 per additional QALY] –For otherwise healthy or high risk unvaccinated adults, oseltamivir cost-effective. [prob(CE)>0.5 at £30,000 per additional QALY]

71 OVERALL SUMMARY POLICY IN UK POST ASSESSMENT: For prevention: –Recommends vaccination of all high-risk individuals –Recommends use of oseltamivir for post- exposure prophylaxis (PEP) in high risk individuals aged 13 years or older who are not effectively protected # by vaccination when influenza A or B is circulating in the community (i.e. who have been exposed to someone with ILI & are able to begin prophylaxis within 48 hours of exposure) [ # “ Not effectively protected by vaccination” includes people not vaccinated or for whom vaccination is contraindicated or has yet to take effect, or vaccination carried out but vaccine not well matched to strain of virus circulating.]

72 OVERALL SUMMARY POLICY IN UK POST ASSESSMENT: For treatment: –Recommends use of zanamivir & oseltamivir to treat high-risk adults when influenza A or B is circulating in the community & treatment can be administered within 48 hours of onset of symptoms. –Recommends otherwise healthy individuals to stay at home & take medicines from the chemist (pharmacist) to relieve the symptoms.

73 REFERENCES Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. British Medical Journal, 2003; 326: Turner DA, Wailoo A, Nicholson K, Cooper NJ, Sutton AJ, Abrams KR. Systematic review and economic modelling of the neurominidase inhibitors for the prevention and treatment of influenza A and B. Health Technology Assessment (Also final report for National Institute for Clinical Excellence (NICE))


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