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

CLINICAL & COST-EFFECTIVENESS OF NEURAMINIDASE

INHIBITORS FOR THE TREATMENT &

PREVENTION OF INFLUENZANicola Cooper, PhD & Alex Sutton,

PhDCentre for Biostatistics and Genetic

Epidemiology, Department of Health Sciences, University of

Leicester, UK.http://www.hs.le.ac.uk

Clinical Trials Research Unit, University of Auckland, December 2003

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

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)

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

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.

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 DiskhalerTM.

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

SYSTEMATIC REVIEW & META-ANALYSES OF

EFFECTIVENESS OF NIs FOR TREATMENT &

PREVENTION OF INFLUENZA

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 31st Dec 2001

– Evaluated treatment or prevention of naturally occurring flu with zanamivir or oseltamivir (using formulation & dosage licensed for clinical use)

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.

TREATMENT

TREATMENT: Primary Endpoints

• Median time to alleviation of symptoms– Measured in ½ days for zanamivir & hours for

oseltamivir

Symptoms alleviated occurs when the following hold for at least 24 hours: Zanamvir Oseltamivir

Feverishness None None or Mild Headache None or Mild None or Mild

Sore Throat None or Mild None or Mild Cough None or Mild None or Mild

Muscle Aches (Myalgia) None or Mild None or Mild Fatigue None or Mild

Nasal Congestion None or Mild Temperature <37.8C (100F)

TREATMENT

Potentially relevant RCTs identified in published literature and/or databases

(n=44 zanamivir, n=18 oseltamivir)

Relevant for inclusion in meta-analysis


Potentially for inclusion in meta-analysis


RCTs with data in correct format

(n=8a zanamivir, n=9 oseltamivir)aNAIA2005 and NAIB2005 combined into one trial

Pharmacokinetics, safety, tolerability studies (n=9 zanamivir, n=0 oseltamivir)

Experimental influenza (n= 8 zanamivir, n=3 oseltamivir )

Non-English (n= 3 zanamivir, n=0 oseltamivir )

Trial on-going (n = 2 zanamivir, n=0 oseltamivir )

Non-comparable endpoint (n=6 zanamivir, 1 oseltamivir )

Dosage differed from licensed (n= 3 zanamivir, n=0 oseltamivir )

Limited data – abstract or company trial report only with no measure of uncertainty for meta-analysis and/or combined patient groups (n= 4 zanamivir, n=5 oseltamivir )

TREATMENT: Systematic review

TREATMENT: Zanamivir

Trial Age Group (years)

% High-risk

% influenza positive

% Vaccinated

Interventions Jadad Score

NAIA2005 NAIB2005

13 0% 63% 0% 144 Placebo 132 Zanamivir

4

NAIB2007 13 13% 62% Not reported

183 Placebo 188 Zanamivir

Lack of information

NAIB3001 12 17% 71% 6% 228 Placebo 227 Zanamivir

5

NAIA3002 12 14% 73% Not reported

365 Placebo 412 Zanamivir

Lack of information

NAIB3002 12 9% 78% 4% 182 Placebo 174 Zanamivir

5

NAI30008 12 100% 60% 23% 263 Placebo 262 Zanamivir

5

NAI30009 5–12 8% 73% 2% 247 Placebo 224 Zanamivir

3

NAI30010 5 >7% 49% 10% 158 Placebo 163 Zanamivir

4

TREATMENT: Zanamivir (ITT)

Population Zanamivir Placebo Absolute Median Difference95% CI

Weight % Median differencein days (95% CI)e : median(se) e : median(se)

0-48 48 96-960-2 2 4-4

HoursDays

Favours PlaceboFavours Zanamivir

e=Number of individuals whose symptoms are alleviated at the end of the trial

Otherwise healthyNAIA/B2005NAIB3001NAIA3002NAIB3002NAI30010

123 : 3.5(0.3)156 : 5.0(0.4)323 : 5.0(0.2)142 : 5.0(0.4)139 : 4.5(0.2)

134 : 4.5(0.3)146 : 6.0(0.3)266 : 5.0(0.3)133 : 6.5(0.6)136 : 5.5(0.4)

Combined (95% CI)

23.619.027.211.219.0

-1.00 (-1.78 to -0.22)-1.00 (-1.94 to -0.06)0.00 (-0.67 to +0.67)-1.50 (-2.88 to -0.12)-1.00 (-1.94 to -0.06)-0.78 (-1.31 to -0.26)

High-riskNAIB3001NAIA3002NAIB3002NAI30008NAI30010

32 : 5.0(0.5)42 : 7.5(1.5)12 : 9.0(3.0)226 : 5.5(0.3)9 : 5.8(1.2)

24 : 7.0(1.4)53 : 6.0(0.9)15 : 11.5(1.4)222 : 6.5(0.5)11 : 6.5(2.5)

Combined (95% CI)

10.88.32.375.23.4

-2.00 (-4.96 to +0.96)1.50 (-1.88 to +4.88)-2.50 (-8.96 to +3.96)-1.00 (-2.12 to +0.12)-0.75 (-6.00 to +4.50)-0.93 (-1.90 to +0.05)

ChildrenNAI30009 213 : 4.0(0.2) 217 : 5.0(0.2)

Combined (95% CI)100.0 -1.00 (-1.52 to -0.48)

-1.00 (-1.52 to -0.48)

• Median time to symptoms alleviated

Population Zanamivir Placebo Absolute Median Difference95% CI

Weight % Median differencein days (95% CI)e : median(se) e : median(se)

0-48 48 96-960-2 2 4-4

HoursDays

Favours PlaceboFavours Zanamivir


Otherwise healthyNAIA/B2005NAIB3001NAIA3002NAIB3002NAI30010

80 : 3.5(0.3)117 : 4.5(0.2)245 : 5.0(0.2)111 : 5.0(0.4)68 : 4.5(0.2)

83 : 4.5(0.5)104 : 6.0(0.4)190 : 6.0(0.3)101 : 6.5(0.7)71 : 5.5(0.3)

Combined (95% CI)

18.533.22.419.526.3

-1.00 (-2.56 to +0.56)-1.50 (-2.66 to -0.34)-1.00 (-5.33 to +3.33)-1.50 (-3.02 to +0.02)-1.00 (-2.31 to +0.31)-1.26 (-1.93 to -0.59)

High-riskNAIB3001NAIA3002NAIB3002NAI30008NAI30010

21 : 5.0(0.6)32 : 5.5(1.8)11 : 9.0(2.2)142 : 5.0(0.3)4 : 4.3(0.7)

17 : 8.0(2.8)38 : 6.0(1.1)14 : 11.5(1.6)134 : 7.0(0.5)6 : 10.5(6.4)

Combined (95% CI)

3.96.84.284.36.3

-3.00 (-8.52 to +2.52)-0.50 (-4.68 to +3.67)-2.50 (-7.79 to +2.79)-2.00 (-3.19 to -0.81)-6.25 (-18.76 to +0.75)-1.99 (-3.08 to -0.90)

ChildrenNAI30009 158 : 4.0(0.2) 161 : 5.0(0.2)

Combined (95% CI)100.0 -1.00 (-1.60 to -0.40)

-1.00 (-1.60 to -0.40)

TREATMENT: Zanamivir (FLU +ve)

• Median time to symptoms alleviated

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

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)

TREATMENT: Oseltamivir

Trial Age Group (years)

% High-risk

% influenza positive

% Vaccinated

Interventions Jadad Score

WV15670 18–65 0% 65% 0% 238 Placebo 243 Oseltamivir

5


5


5

WV15812 WV15872 WV15819 WV15876 WV15978

Commercial in Confidence Commercial in Confidence Commercial in Confidence Commercial in Confidence Commercial in Confidence


4

TREATMENT: Oseltamivir (ITT)

• Median Time to symptoms alleviated

Population Oseltamivir Placebo Absolute Median Difference95% CI

Weight % Median differencein hours (95% CI)e : median(se) e : median(se)

0-48 48 96-960-2 2 4-4

HoursDays

Favours PlaceboFavours Oseltamivir


Otherwise healthyWV15670WV15671WV15730

211 : 97.6(9.9)182 : 76.3(6.4)27 : 74.5(8.2)

191 : 116.1(7.6)178 : 97.0(5.3)21 : 109.8(31.2)

29.366.24.4

-18.50 (-43.02 to -6.02)-20.68 (-37.00 to -4.36)-35.33 (-98.46 to +27.80)-20.69 (-33.97 to -7.41)

High-riskWV15812WV15872WV15819WV15876WV15978

Commercial in confidence dataCommercial in confidence dataCommercial in confidence dataCommercial in confidence dataCommercial in confidence data

Combined (95% CI) -8.33 (-33.69 to +17.03)

ChildrenWV15758 319 : 125.7(5.1) 310 : 104.8(5.6)

Combined (95% CI)100.0 -20.90 (-35.70 to -6.13)

-20.90 (-35.70 to -6.13)

TREATMENT: Oseltamivir (FLU +ve)

• Median Time to symptoms alleviatedPopulation Oseltamivir Placebo Absolute Median Difference

95% CIWeight % Median difference

in hours (95% CI)e:median(se) e:median(se)

0-48 48 96-960-2 2 4-4

HoursDays

Favours PlaceboFavours Oseltamivir


Otherwise healthyWV15670WV15671WV15730

140 : 87.4(7.8)112 : 71.5(5.6)17 : 78.2(10.6)

133 : 116.5(8.5)113 : 103.3(7.9)15 : 143.9(24.8)

Combined (95% CI)

38.554.57.0

-29.08 (-51.65 to -6.51)-31.75 (-50.73 to -12.77)-65.75 (-118.69 to -12.81)-33.10 (-47.10 to -19.10)

High-riskWV15812WV15872WV15819WV15876WV15978

Commercial in confidence dataCommercial in confidence dataCommercial in confidence dataCommercial in confidence dataCommercial in confidence data

Combined (95% CI) -10.91 (-45.04 to +23.22)

ChildrenWV15758 210 : 137.0(5.4) 196 : 101.3(7.1)

Combined (95% CI)100.0 -35.80 (-53.36 to -18.24)

-35.80 (-53.36 to -18.24)

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

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)

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

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

PREVENTION

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

PROPHYLAXIS

Potentially relevant RCTs identified in published literature and/or databases


Relevant for inclusion in meta-analysis


Potentially for inclusion in meta-analysis


RCTs with data in correct format(n=4a zanamivir, n=4 oseltamivir)aNAIA2009 and NAIB2009 combined into one trial

Pharmacokinetics, safety, tolerability studies (n=1 zanamivir, n=0 oseltamivir)

Non-English (n= 0 zanamivir, n=1 oseltamivir )

Unblind (n=1 zanamivir, n=0 oseltamivir)

Dosage differed from licensed (n=2 zanamivir, n=0 oseltamivir )

None or only limited data from abstracts available (n= 3 zanamivir, n=1 oseltamivir )

PREVENTION: Systematic review

PREVENTION: Zanamivir

Trial Age group

% High risk

% Vaccinated

Interventions Trt Duration

Jadad score

Seasonal prophylaxis in a healthy population NAIA3005 18-64

years 0% 15% 554 placebo

553 Zanamivir 4 weeks 4

Post-exposure prophylaxis in the household setting NAIA2009

NAIB2009 13-65 years

Not reported

0% 144 placebo 144 Zanamivir

5 days 3

NAI30010 Families >6% 16% 423 placebo 414 Zanamivir

10 days 4

PREVENTION: Zanamivir• 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

Trial % Vaccinated

Number of influenza cases

Odds ratio (95% CI)

Seasonal prophylaxis in a healthy population NAIA3005 15% 34 out of 554 placebo

11 out of 553 Zanamivir 0.31 (0.14 to 0.64)

Post-exposure prophylaxis in the household setting (pooled odds ratio 0.19 (0.09 to 0.38))

NAIA2009 NAIB2009

0% 9 out of 144 placebo 3 out of 144 Zanamivir

0.27 (0.07 to 1.05)

NAI30010 16% 40 out of 423 placebo 9 out of 414 Zanamivir

0.16 (0.07 to 0.37)

PREVENTION: Oseltamivir

Trial Age group

% High risk

% Vaccinated

Interventions Trt Duration

Jadad score

Seasonal prophylaxis in the elderly residential home setting WV15825 64-96

years 100% 80% 272 placebo

276 oseltamivir 6 weeks 4

Seasonal prophylaxis in a healthy population WV15673

18-65 years

0% 0% 268 placebo 268 oseltamivir

6 weeks 5

WV15697

18-65 years


6 weeks 5

Post-exposure prophylaxis in the household setting WV15799

12-85 years.


7 days 4

PREVENTION: Oseltamivir• 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

Trial % Vaccinated Number of influenza cases Odds ratio (95% CI)

Seasonal prophylaxis in the elderly residential home setting WV15825 80% 12 out of 272 placebo

1 out of 276 oseltamivir 0.08 (0.01 to 0.61)

Seasonal prophylaxis in a healthy population (pooled odds ratio 0.26 (0.08 to 0.84))

WV15673

0% 19 out of 268 placebo 3 out of 268 oseltamivir

0.15 (0.04 to 0.51)

WV15697

0% 6 out of 251 placebo 3 out of 252 oseltamivir

0.49 (0.12 to 1.99)

Post-exposure prophylaxis in the household setting WV15799

13% 34 out of 462 placebo

4 out of 493 oseltamivir 0.10 (0.04 to 0.29)

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

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.

Time to symptoms alleviated (hours)

pro

po

rtio

n w

ith s

ymp

tom

s

0 100 200 300 400 500

0.0

0.2

0.4

0.6

0.8

1.0

control75mg bid

Last observation censored =>

mean undefined

• 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

mediant

)5.0ln(hazard Mean = 1/

Var = 1/2

FURTHER ISSUES

Exponentially extended survivor function

Su

rviv

al p

rob

ab

ility

analysis time0 250 500 750 1000 1250 1500

0

.2

.4

.6

.8

1

Exponentially extending the survival curve to zero

Exponentially extending the survival curve to zero

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

COST-EFFECTIVENESS OF NEURAMINIDASE

INHIBITORS FOR THE TREATMENT &

PREVENTION OF INFLUENZA

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

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

TREATMENT

TREATMENT: Drug Costs•Zanamivir:

• Dry powder for inhalation disks containing 4 blisters of zanamivir 5mg/blister, net price 5 disks with Diskhaler® device = £24.00

• 10mg twice daily for 5 days = £24.00+VAT

•Oseltamivir:

• Capsules, grey/yellow, oseltamivir (as phosphate) 75 mg, net price 10-cap pack = £18.18.

• 75mg twice daily for 5 days = £18.18+VAT

(NOTE: £1 = 2.65NZ$)

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


Decision to consult health care provider

Outcome of illness

The policy decision Does the individual have influenza

Treatment options

No antiviral treatment available

Make antivirals available

Amantadine available

NIs available

Zanamivir 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

Has influenza A

Has influenza B



Recover


Recover

Complication/DeathNI prescribed

Recover

Complication/Deathno NI prescribed

Before 48 hours

Recover

Complication/DeathNI prescribed

Recover

Complication/Deathno NI prescribed

After 48hours

Presents to GP

Recover

Complications/DeathDoes not present to GP

Has influenza

Does NOT have influenza

NI available

Standard care

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

TREATMENT: Healthy Adults

Vs. standard care

Incremental cost (95% CI)

Incremental Utility (95% CI)

Mean cost per QALY

Mean cost per illness day avoided

oseltamivir £0.895 (0.416 to 1.701)

0.000047 (-0.000148 to 0.000262)

£19,015 £20.01

zanamivir £1.290 (0.606 to 2.450)

0.000041 (-0.000156 to 0.000254)

£31,529 £33.24

• Base-Case Results

• Extrapolated Results Vs.

standard care



Mean cost per QALY

oseltamivir £0.878 (0.872 to 0.885)

0.000186 (0.000183 to 0.000188) £4,729

zanamivir £1.278 (1.268 to 1.287)

0.000144 (0.000141 to 0.000146) £8,884

TREATMENT: Healthy Adults

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80 90 100

Willingness to pay for an additional QALY (£'000s)

Pro

ba

bili

ty c

os

t-e

ffe

cti

ve

zanamivir_basecase

oseltamivir_basecase

zanamivir_extrapolated

oseltamivir_extrapolated

0 27 54 81 108 135 161 188 215 242 269

UK£

NZ$Willingness to pay for additional QALY (£’000s)

TREATMENT: High Risk

Vs. standard care



Mean cost per QALY


oseltamivir £0.712 (0.260 to 1.599)

0.000032 (-0.000100 to 0.000187)

£22,502 £24.25

zanamivir £0.960 (0.353 to 2.148)

0.000056 (-0.000067 to 0.000221)

£17,289 £18.25

• Base-Case Results

Vs. standard care



Mean cost per QALY

oseltamivir £0.505 (0.500 to 0.510)

0.000168 (0.000165 to 0.000167)

£3,016

zanamivir £0.696 (0.689 to 0.703)

0.000230 (0.000227 to 0.000232)

£3,029

• Extrapolated Results

TREATMENT: High Risk

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80 90 100


Pro

ba

bili

ty c

os

t-e

ffe

cti

ve

zanamivir_basecase




0 27 54 81 108 135 161 188 215 242 269

UK£


TREATMENT: Children•Base-Case Results

Vs. standard care



Mean cost per QALY


oseltamivir £1.661 (0.874 to 2.856)

0.000085 (-0.000254 to 0.000439)

£19,461 £24.94

zanamivir £2.222 (1.165 to 3.838)

0.000072 (-0.000269 to 0.000424)

£30,825 £38.86

• Extrapolated Results

Vs. standard care



Mean cost per QALY

oseltamivir £1.663 (1.653 to 1.673)

0.000147 (0.000143 to 0.000151)

£11,318

zanamivir £2.230 (2.216 to 2.243)

0.000117 (0.000113 to 0.000120)

£19,127

TREATMENT: Children

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80 90 100


Pro

ba

bili

ty c

ost

-effe

ctiv

e

zanamivir_basecase




0 27 54 81 108 135 161 188 215 242 269

UK£


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


• Otherwise Healthy Adults (similar results for other population groups)

010,00020,00030,00040,00050,00060,00070,00080,00090,000

100,000

0 0.25 0.5 0.75 1

Proportion of ILI which is influenza

ICE

R

Oseltamivir

Zanamivir

(i.e. diagnostic accuracy)


• Otherwise Healthy Adults

020000400006000080000

100000120000140000160000

0.0 0.3 0.5 0.8 1.0

Proportion of individuals given drug after 48 hours

ICE

R

Oseltamivir

Zanamivir

(Assumed NIs ineffective if given after 48 hours)


-300000-250000-200000-150000-100000-50000

050000

100000150000200000

0.0 0.3 0.5 0.8 1.0

Proportion of individuals who present to GP if NIs available

ICE

R

Oseltamivir

Zanamivir

• Otherwise Healthy Adults

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

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

PREVENTION

PREVENTION: Drug Costs•Zanamivir:

• Dry powder for inhalation disks containing 4 blisters of zanamivir 5mg/blister, net price 5 disks with Diskhaler® device = £24.00

• 10mg once daily for 6 weeks = £100.8+VAT

•Oseltamivir:

• Capsules, grey/yellow, oseltamivir (as phosphate) 75 mg, net price 10-cap pack = £18.18.

• 75mg once daily for 6 weeks = £76.36+VAT

(NOTE: £1 = 2.65NZ$)

DECISION MODEL: Prevention

• Seasonal Prophylaxis Strategy (SPS)

PREVENTION (SPS): Healthy Adults

Strategy Incremental cost (95% CI)


Mean cost per QALY


Compared to no intervention Vaccine

prophylaxis £7.532 (£7.528 to £7.535)

0.00154 (0.00152 to 0.00155) £4,904 £22

Zanamivir prophylaxis

£124.517 (£124.515 to £124.519)

0.00030 (0.00030 to 0.00031) £411,901 £705

Oseltamivir prophylaxis

£100.054 (£100.051 to £100.057)

0.00032 (0.00031 to 0.00032) £315,016 £519

Compared to Vaccine only Vaccine and

Zanamivir £124.769 (£124.768 to £124.770)

0.000063 (0.000062 to 0.000064) £1,994,453 £2,250

Vaccine and Oseltamivir

£100.321 (£100.320 to £100.322)

0.000065 (0.000064 to 0.000066) £1,548,261 £1,631

PREVENTION (SPS): High Risk



Mean cost per QALY



prophylaxis £2.223 (£2.171 £2.275)

0.00538 (0.00534 to 0.00542) £413 £9


£123.450 (£123.439 to £123.462)

0.00115 (0.00114 to 0.00116) £107,021 £568


£98.921 (£98.907 to £98.936)

0.00121 (0.00120 to 0.00122) £81,519 £418


Zanamivir £124.35 (£124.28 to £124.43)

0.000397 ( 0.000393 to 0.000401) £313,046 £314


£99.88 (£99.80 to £99.96)

0.000418 ( 0.000413 to 0.000423) £238,941 £245

PREVENTION (SPS): Children



Mean cost per QALY



prophylaxis £7.205 (£7.201 to £7.209)

0.00123 (0.00117 to 0.00128) £5,882

£9


£124.461 (£124.459 to £124.464)

0.00043 (0.00042 to 0.00043) £291,482

£393


£100.017 (£100.015 to £100.020)

0.00043 (0.00042 to 0.00043) £234,235

£316


Zanamivir £124.74 (£124.73 to £124.74)

0.000151 (0.000148 to 0.000154) £824,953 £1,124


£100.29 (£100.29 to £100.29)

0.000151 (0.000148 to 0.000154) £663,290 £903

DECISION MODEL: Prevention

•Post-Exposure Prophylaxis Strategy (PEP)(Note: only oseltamivir considered as zanamivir not licensed)

PREVENTION (PEP)

Vaccinated Oseltamivir vs nothing

£'s per QALY £'s per case

avoided Otherwise healthy adults 162,556 1,316 High-risk 29,399 733 Residential care 3,183 469

Unvaccinated Oseltamivir vs nothing

£'s per QALY £'s per case

avoided Otherwise healthy adults 28,271 374 High-risk 7,216 325 Residential care Oselt dominates Oselt dominates

PREVENTION (PEP): Healthy Adults

0

0.2

0.4

0.6

0.8

1

0 20,000 40,000 60,000 80,000 100,000

Willingness-to-pay per QALY (£'s)

Pro

bab

ilit

y co

st-e

ffec

tive

No PEP

Ose

• Otherwise healthy unvaccinated adults

0 54,000 108,000 161,000 215,000 269,000

UK£

NZ$Willingness to pay for additional QALY

PREVENTION (PEP): High Risk

• High-risk unvaccinated adults

0

0.2

0.4

0.6

0.8

1

0 20,000 40,000 60,000 80,000 100,000


Pro

bab

ilit

y C

ost

-eff

ecti

ve

No PEP

Ose

0 54,000 108,000 161,000 215,000 269,000

UK£

NZ$Willingness to pay for additional QALY

PREVENTION (PEP): High Risk

• High-risk vaccinated adults

0

0.2

0.4

0.6

0.8

1

0 20,000 40,000 60,000 80,000 100,000


Pro

bab

ilit

y C

ost

-eff

ecti

ve

No PEPOse

Willingness to pay for additional QALY0 54,000 108,000 161,000 215,000 269,000

UK£

NZ$

PREVENTION (PEP): Sensitivity

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

0.05 0.1 0.15

Attack rate

Co

st-e

ffect

ive

ne

ss r

atio

(£

)

healthy/unvaccinated

high-risk/unvaccinated

high-risk/vaccinated

(i.e. probability that an individual exposed to someone with ILI develops influenza)

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]

OVERALL SUMMARYPOLICY 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.]

OVERALL SUMMARYPOLICY 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.

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: 1235.

• 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 2003. (Also final report for National Institute for Clinical Excellence (NICE))

Documents

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