Cost-effectiveness of paediatric seasonal influenza vaccination in
England and Wales
RJ PitmanICON Health Economics, Oxford, UK
Canadian Public Health Association Conference
Toronto, CanadaMay, 2014
Why conduct cost-effectiveness analyses?
• Health policy is formulated to maximise the health of the population
• Budgets are finite
• So how do we most efficiently use these limited resources?
Incremental costs and benefits
Choice : PolicyA or B ?
Cost
Costs OutcomesPolicy A
Costs OutcomesPolicy B
Benefit
Does the extra benefit justify the extra cost ?Does the extra benefit justify the extra cost ?
Cost-effectiveness plane
New treatment more effective
New treatment less effective
New treatment more costly
New treatment less costly
New treatment dominates
Old treatment dominates New treatment more costly and more effective
New treatment less costly and less effective
Cost-effectiveness threshold £20,000 per QALY
QALYs gained
Cost
Cost-effectiveness and opportunity cost
£40,000Price = P*£20,000 per QALY
£60,000Price > P*£30,000 per QALY
2
£20,000Price < P*£10,000 per QALY
1
Net Health Benefit1 QALY
3
Net Health Benefit-1 QALY
The region of cost-effectivenessDifference in cost
Difference in effect
Cost-eff
ective
ness th
resh
old
Region of c
ost-eff
ective
ness
Cost-effectiveness plane
0.0 0.2 0.4 0.6 0.8 1.0
05
00
01
00
00
15
00
02
00
00
QALYs
co
sts
l
l = cost-effectiveness threshold
Cost effectiveness acceptability curvePr
obab
ility
mos
t cos
t-effe
ctive
Cost-effectiveness threshold (l)
100%
50%
20%
80%
New Treatment
Current Treatment
Moving from the ICER to net benefit
Threshold defines value of health outcome
Standard ICER decision rule:ΔC/ΔQ < λ Where λ is the threshold
Net monetary benefit:(ΔQ x λ) – ΔC > 0
Net health benefit:ΔQ – (ΔC/ λ) > 0
0 5000 10000 15000
-1.0
-0.5
0.0
0.5
1.0
costs
NH
BQ
Cmax Q
Influenza vaccinationIn England and Wales vaccination against seasonal influenza was only offered if:
• Over six months old and at an increased risk of influenza complications
• This included everyone over the age of 65 years and anyone younger who falls into a predefined risk group
Influenza vaccination
• Base case
Influenza vaccination (status quo)• 6mo - <65yrs at risk of influenza related
complications• 65+yrs
vs
Paediatric influenza vaccination• Status quo + 2yrs - <19yrs
The components of a vaccine cost-effectiveness model
Pitman et al. Vaccine (2012) 30: 1208-1224
Who Acquires Infection From Whom (WAIFW) matrix
Mossong J et al. PLoS Med (2008) 5: 381-391
The components of a communicable disease model
Vynnycky E et al. Vaccine (2008) 26: 5321-5330
Deaths
Hospitalization
Outpatient visits
Primary care physician visits
Symptomatic disease
Influenza infections
Pitman et al. J Infect (2007) 54: 530-538
AH1N1 AH3N2 B(Yam) B(Vic)
Incremental cost effectiveness analysis over 15 years, at 50% uptake
Policy option QALYs lost
(millions)
Cost (millions)
Incremental QALYs
(millions)
Incremental Cost
(millions)
ICER
No Vaccination 10.25 £8,123 Dominated
Current policy 2.43 £6,730 7.82 -£1,393 Cost saving
Current policy + vaccination in 2 - 4 year olds
1.75 £6,759 0.69 £29 £43
Current policy + vaccinationin 2 - 18 year olds
0.20 £7,870 1.55 £1,111 £719
15 year cumulative burden of influenza, at 50% uptake
Current practice (CP)
CP + 2-4 yrs
No vaccination
CP + 2-18 yrs
Pitman et al. Vaccine (2013) 31: 927-942
Cost effectiveness acceptability curves, using 15 year cumulative data, at 50%
No vaccination
Current policy
CP + 2-4 yrs
CP + 2-18 yrs
Pitman et al. Vaccine (2013) 31: 927-942
Conclusions• Paediatric vaccination is likely to result in
substantial health savings both within and beyond the vaccinated cohorts of children
• While there is considerable uncertainty in the system, annual paediatric influenza vaccination was consistently estimated to be cost-effective
Thank You
Contributors:
Lisa Nagy – ICON Health Economics
Mark Sculpher – York Centre for Health Economics
Reserve slides
Decisions when a treatment does not dominate
• Assessing the opportunity cost– What existing treatments will have to be displaced?– What health benefits will be forgone?
• A rule of thumb– How does the extra cost of a unit of benefit compare
with previous decisions?
• What is society willing to pay for an extra unit of benefit?– Increase insurance premiums/taxation to provide new intervention
Influenza virus• Constantly changing virus• Comes in two types: A and B• Influenza A
– Responsible for pandemics– Has numerous subtypes
• A(H1N1) – 1918• A(H2N2) – 1957• A(H3N2) – 1968• A(H1N1/09) – 2009
PHIL ID #11823, Dan Higgins, CDC
Burden of influenza in England & Wales
The annual health burden of seasonal influenza is considerable
Very roughly:
• 1 million General Practice consultations
• 25,000 Hospitalisations
• 20,000 Deaths
Pitman R et al, J Infect, 2007, 54, 530-538
Estimated annual rate of influenza A relatedprimary care consultations
Pitman R et al, J Infect, 2007, 54, 530-538
Estimated annual rate of influenza A relatedhospitalisations
Pitman R et al, J Infect, 2007, 54, 530-538
Estimated annual rate of influenza A relateddeaths
Pitman R et al, J Infect, 2007, 54, 530-538
The debate: Who should we be targeting?
• Those at greatest risk of complications?
• Or a combination of both?
• Those most likely to transmit the virus?
Influenza virion TEM: #10073 CDC/ Dr. Erskine. L. Palmer; Dr. M. L. Martin
Objective
• To assess the cost effectiveness of adopting a policy of routine childhood influenza vaccination in the England and Wales, taking account of the dynamics of transmission and indirect protection (herd protection)
SusceptibleImmune following infectionVaccinatedProtected by herd immunity
Herd Immunity
Current policyHigh risk groups• 65+ years old• 6 months – 64 years old in the following groups:
– Residents of nursing or residential homes for the elderly and other long-stay facilities
– or with the following conditions:• Chronic respiratory disease (includes asthma treated with continuous or
repeated use of inhaled or systemic corticosteroids or asthma with previous exacerbations requiring hospital admission)
• Chronic heart, liver or renal disease• Chronic neurological disease• Diabetes mellitus• Immunosuppression because of disease or treatment • HIV infection (regardless of immune status)
– Carers of the above– Health care workers– Pregnant women
Methods: Univariate sensitivity analysis• Population mixing
– Homogeneous (random)
• Basic reproductive rate– 1.4– 2.2
• No Seasonality
• Seeding– 10 / year / age band; 5 – 50 years of age
• Vaccine Coverage– 10%– 50%– 80%
Status quo
• Elderly (65+yrs) and at risk groups vaccinated
• Annually from 2000 onwards
Age groups in
model%
efficacy 1
% uptake in total
population2
0 - <1 60% 0.1%
1 - <2 60% 0.1%
2 - <5 60% 1.4%
5 - <11 60% 1.4%
11 - <19 60% 1.4%
19 - <50 75% 5.6%
50 - <65 75% 5.6%
65+ 50% 73.5%
1. Jefferson T. et al Cochrane Database Syst Rev, CD004879 2008Jefferson T. et al Cochrane Database Syst Rev, CD001269 2007Rivetti, D. et al Cochrane Database Syst Rev, CD004876 2006
2. Health Protection Agency data
Paediatric vaccination • Annually from 2009 onwards• Efficacy 80% 1,2
• Coverage 50%• Target age groups
– Pre-school: 2 - <5– Primary School age: 5 - <11– Secondary school age: 11-<19
1. Jefferson T. et al Cochrane Database Syst Rev, CD004879 2008Jefferson T. et al Cochrane Database Syst Rev, CD001269 2007Rivetti, D. et al Cochrane Database Syst Rev, CD004876 2006
2. Belshe, R. B. et al N Engl J Med, 2007, 356, 685-696Rhorer, J. et al Vaccine, 2009, 27, 1101-1110
Cost-effectiveness analysis
Assumptions
• Health Service (NHS) perspective
• 3.5% discount rate applied to both costs and benefits
Costs• Vaccination
– GP consultation– Vaccine price point
• TIV – mean list price• LAIV = TIV
• Health outcomes – age stratified mean cost of influenza related– GP consultation– Hospitalisation
• Costs inflated to 2009 prices, where appropriate
Outcomes
• Averted– General practice consultations– Hospitalisations– Deaths
• Quality adjusted life years– QALY decrements based on estimates from 2003
HTA report1
– Adult QALYs used
1. Turner D et al Health Technol Assess. 2003; 7: 1-170
Sensitivity analyses
• Univariate sensitivity analysis• Probabilistic Sensitivity analysis
– Variation in probabilities: beta distribution– Variation in costs and utility decrements: gamma
distribution– Probability cost-effective: Cost-effectiveness
acceptability curve (CEAC)– Probability of option with highest net benefit being cost-
effective: Cost-effectiveness acceptability frontier (CEAF)• Extreme value analysis
Extreme Value Analysis• The transmission coefficient (R0 of 1.4, 1.8 and 2.2)• Infectious cases seeded into the population each
year (50, 100, 150)• Duration of natural immunity (influenza A: 5 years, 6
years, 7 years; influenza B: 11 years, 12 years, 13 years)
• Duration of infectiousness (1 day, 2 days, 5 days)• Percentage of infected individuals that experience
symptoms (55%, 64%, 73%)• Latent period (1 day, 2 days, 3 days)• Duration of vaccine induced immunity (Flu A: 3
years, 6 years, 7 years; Flu B: 6 years, 12 years, 13 years)
Simulated influenza Vaccination of elderly
Paediatric vaccination
Results: Sensitivity of the 15 year cumulative averted influenza cases per 100,000 population,
assuming 80% coverage of 2 to 18 year old children with LAIV in addition to current practice
Extreme value analysis
Influenza A Influenza B
The cost of an influenza related GP consultation
General Practice Research Database 2000 - 2009Personal and Social Services Research Group Report 2008
Age Group GP consultations0-11 mo £8812-23 mo £8824-59 mo £655-10 years £5411-18 years £6619-49 years £8550-64 years £10165+ years £100
MedianMedian
CostLength
of Stay
0 - 10 yr 6 1,606
11 - 18 yr 6 1,634
19 - 49 yr 6 1,662
50 - 64 yr 7 1,983
65+ yr 19 5,354
All Ages 8 2,123
The cost of an influenza related hospitalisation
Hospital Episode Statistics 2005-06NHS National Schedule of Reference Costs 2007-08
Annual primary care and hospitalisation costs of influenza in England & Wales
Total annual cost ~ £175,000,000
Hospital Episode Statistics 2005-06NHS National Schedule of Reference Costs 2007-08General Practice Research DatabasePerson and Social Services Research Unit annual reportPitman R et al, J Infect, 2007, 54, 530-538
Results: Sensitivity of ICER to time horizon, at 50% uptake
15 year estimated cumulative burden of influenza, at increasing levels of paediatric
vaccine uptake
Cost effectiveness acceptability frontier, based on 15 year cumulative data, at 50% uptake
Limitations
• Model incidence calibrated against Tecumseh data (1970s, US data)
• It was not possible to benchmark the model simulations against actual European data on influenza virus infection rates. Obtaining such sero-epidemiological data will help reduce uncertainty within the parameter estimates
• High level of uncertainty in many of the parameters
• Vaccination behaviour
• Simple treatment of antigenic drift
• Cross-protection
Is there evidence for herd immunity?
Tecumseh, Michigan, USA
1968
HONG KONG FLUAH3N2
Tecumseh studyTecumseh• Population ~10,000• Respiratory illness surveillance
project since 1965• ~360 families followed at any one
time– 60% random selection– 40% selected with chronic respiratory
disease & matched controls– Followed for one year then replaced
with another family• Vaccinated 85.8% school age children
(Elementary through to High School)• Monovalent vaccine (A2/Aichi/2/68)
vs. AH3N2 virus (Hong Kong Flu)• School absenteeism monitored along
with respiratory illness surveillance
Adrian• Population ~20,000• 12 miles south of Tecumseh• Significant population interchange• Weekly family surveillance
programme in place• 150 households• Each family followed for 3 weeks• Same questions on respiratory illness
as in Tecumseh• School absence data also collected
Monto AS et al, Bull World Health Organ, 1969, 41, 537-542
Tecumseh study
Two weeks after vaccination began the first isolate of AH3N2 was obtained in Tecumseh
School absenteeism 1968 – ‘69
Monto AS et al, Bull World Health Organ, 1969, 41, 537-542
Incidence of respiratory illness
Monto AS et al, Bull World Health Organ, 1969, 41, 537-542
Age specific weekly mean rate of respiratory illness
0 - 4 5 - 9 10 - 14 15 - 19 20 - 29 30 - 39 40+02468
1012141618 Adrian (adjusted)
Tecumseh
Age group (Years)
Perc
enta
ge p
er w
eek
(Mea
n)
85.8% vaccine coverage
Monto AS et al, J Infect Dis, 1970, 122, 16-25
Japan – paediatric influenza vaccination
• 1962 – 1987 mandatory influenza vaccination of all schoolchildren
• Law relaxed in 1987• Repealed in 1994• Thomas Reichert analysed excess mortality
1949 - 1998
Reichert et al. N Eng J Med 2001;344:889-896
Excess deaths attributed to pneumonia and influenza – 5 year moving average
Reichert et al. N Eng J Med 2001;344:889-896
Population pyramid, Japan, 1950 - 2000
AgeMale Female Male Female1950 2000
Population (thousands) Population (thousands)
Herd immunity demonstrated in randomised control trial in 2010
Loeb et al. JAMA 2010; 303: 943-950
A simple epidemic schematic with replenishment of susceptible individuals
Time
Infe
ction
s
0
= R0
Epidemic curve
Effec
tive
repr
oduc
tive
rate
0
2
1
Effective reproductive rate
Communicable disease epidemiology
Time
Infe
ction
s
0
Epidemic curve
Effec
tive
repr
oduc
tive
rate
0
2
1
Effective reproductive rate
Imm
une
S
Vaccination
Communicable disease epidemiology
Time
Infe
ction
s
0
Effec
tive
repr
oduc
tive
rate
0
2
1
Imm
une
SV
Vaccination
Epidemic curveEffective reproductive rate
Communicable disease epidemiology
Time
Infe
ction
s
0
Effec
tive
repr
oduc
tive
rate
0
2
1
Imm
une
SV
Vaccination
Epidemic curveEffective reproductive rate
Communicable disease epidemiology
Time
Infe
ction
s
0
Effec
tive
repr
oduc
tive
rate
0
2
1
Imm
une
SV
Vaccination
Epidemic curveEffective reproductive rate
Communicable disease epidemiology
Time
Infe
ction
s
0
Effec
tive
repr
oduc
tive
rate
0
2
1
Imm
une
SV
Vaccination
Epidemic curveEffective reproductive rate
Communicable disease epidemiology
Time
Infe
ction
s
0
Effec
tive
repr
oduc
tive
rate
0
2
1
Imm
une
SV
Vaccination
Epidemic curveEffective reproductive rate
Replenishment of susceptibles
Generation of immunity
• Rate of viral spread• R0
• Viral generation time• Vaccination
• Coverage • Frequency• Behaviour
• Loss of effective immunity• Waning immunity• Antigenic drift / shift
• Births
QALYs
• “Generic” measure of health– Applicable to a wide range of clinical areas
• Combines length and quality of life• Utilities used as quality weights:
– Survival = 10 years– Utility score = 0.5– QALYs = 10 x 0.5 = 5 QALYs
Calculation Of QALYsUTILITY
YEARS321
0.9
0.5
4
1 QALY(No treatment)
3.6 QALYs(With treatment)
2.6 QALYs gained
Calculation Of QALYs
YEARS
UTILITY
15105
0.9
0.5
No Treatment
With Treatment
QALYs Gained
A QALY Is A QALYUTILITY
YEARS321
1
0.5
0.3
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