Cost-effectiveness of paediatric seasonal influenza vaccination in England and Wales RJ Pitman ICON...

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

Richard.Pitman@ICONplc.com

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