The Cost Effectiveness of RSV Prophylaxis: Using Decision

Analysis to Build a Better Guideline

Melony E. S. Sorbero, PhD, MS, MPH

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Purpose

• To evaluate the cost effectiveness of current AAP recommendation for use of RSV prophylaxis.

• Focus on premature infants without CLD.

• Identify more cost-effective alternative recommendations.

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Background

• Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract illness in young children.

• Generally resolves uneventfully in otherwise healthy children. • High risk populations may develop severe and sometimes fatal

lower respiratory tract infections.• RSV infection annually contributes up to 126,300 pediatric

hospitalizations in the U.S.• Estimated annual hospitalization costs for RSV pneumonia in

children <=4 years: $300 - $400 million (1998 $)+.• Annual mortality due to RSV in infants and children is

estimated to range from 200 ++ to over 2,700 +++.

(+Howard et al. J of Peds 2000; ++Shay DK et al. J Infect Dis 2001; +++ Institute of Medicine. In:New Vaccine Development: Establishing Priorities: Vol I. Wash DC Nat Aca Press 1986)

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Background

• There may also be long-term health consequences due to severe RSV infections:

– Increased risk of asthma and other respiratory conditions– Duration of increased risk up to 10 years

• A causal relationship between morbidity and severe RSV infection has not been shown.

(Meissner HC at al. Pediatr Infect Dis J. 1999; Sigurs et al. Am J Resp Crit Care Med 2000; Sampalis J Pediatr 2003 )

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Background

• Prematurity increases risk of severe RSV infection.

(Stevens TP et al. Arch Ped Adoles Med 2000)

20.60%

14.60%

11.30%

6.40%

0%

5%

10%

15%

20%

25%

Percent RSV Hospitalization

=< 26 W. 27 - 28 W. > 28 - 30 W. > 30 - 32 W.

Gestational Age at Birth

RSV Hospitalization Rate by Gestational Age at Birth

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Background

• Worldwide RSV epidemics occur yearly– United States: November – April– Peak: January – March (most areas)– Peak: 2 – 3 months earlier (Southeast)

• 80% RSV admissions occur within 4 months discharge from NICU.

42%

27%

15%

41%

0%5%

10%15%20%25%30%35%40%45%

Probability of hospitalization

Jan. Feb. - Apr. May - Aug. Sept. - Dec.Month of Discharge

Respiratory Illness Hospitalization Rate by Month of Discharge from NICU in Infants <= 32 Weeks GA

(Cunningham CK, McMillan JA, Gross SJ Pediatrics 1991)

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Background

• No vaccine available for RSV.

• 2 products available in U.S. for passive immuno-prophylaxis against RSV.

• Respiratory Syncytial virus immunoglobulin intravenous (RSV-IGIV) (RespiGam; MedImmune, Inc, Gaithersburg, MD), containing high-titer RSV antibodies.

• Palivizumab, (Synagis; MedImmune, Inc, Gaithersburg, MD), is a humanized monoclonal antibody that binds to the F-protein of RSV.

• Require monthly treatments during RSV season.

• Synagis less costly and more effective of two.

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American Academy of Pediatrics (AAP) Recommendations for Prophylaxis Use

• Released in 1998; updated in 2003.

• Infants younger than age 2 years who currently receive or have recently required medical therapy for CLD.

• Infant born 28 weeks gestation who are 12 months old at the start of the RSV season.

• Infants born at 29 to 32 weeks who are 6 months old at the start of the RSV season.

• Infants born between 32 and 35 weeks of gestation with risk factors.

(Red Book, 2000)

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Synagis

• Efficacy of Synagis in prevention of severe RSV infection in premature infants without CLD: 82%.

• Synagis is available in 50 and 100 mg vials.• The cost is $725 per 50 mg and $1370 per 100 mg

vial. • Synagis has a shelf life of 6 hours making drug

wastage nearly inevitable.

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Study Design

• Developed decision analytic model.

• Societal perspective.

• Two versions: w/ and w/o asthma.

• Impact of asthma modeled with semi-Markov processes.

• Conducted CEA on models with asthma; CBA on models w/o asthma.

• Seven hypothetical cohorts of premature infants without CLD born at 24 – 32 weeks gestational age (GA).

• Assumed discharged from NICU at 36 weeks post-conceptual age.

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Model Assumptions

• Risk of RSV hospitalization obtained from published literature.– Gestational age specific probabilities – Seasonal pattern of hospitalization

• Efficacy of palivizumab adapted from IMpact study.• Costs: year 2002 dollars• Costs include:

– Hospital costs– Cost of pulmonary clinic visits for Synagis injections – Emergency room visit cost– Drug costs– Cost of hours missed from work by parents for visits and

hospitalization

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Models with Asthma

• Increased risk of asthma varies with chronologic age.• Duration for increased asthma risk: 10 years• Includes quality of life adjustment for asthma.• Incorporates national estimates of annual asthma cost• Future benefits and costs discounted at 3%

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0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

24 - 26 27 28 29 - 30 31 32

Gestational Age at Birth (Weeks)

Expe

cted

Cos

ts ($

)

$ 2,184

$ 678

$ 7,298$ 8,000

$ 4,092

Synagis: AAP Recommendations:Infants: = < 28 weeks if = < 12 months old at the start of the RSV season

Synagis: AAP Recommendations:Infants: 29 - 32 weeks if = < 6 months old at the start of the RSV season

Synagis

NoSynagis

$ 1,548

Effect of Gestational Age on Expected Costs

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Incremental Cost-Effectiveness Ratio

• Incremental cost-effectiveness ratio (ICER):Cost1 – Cost2 =

QALY1 – QALY2

Cost (Synagis) – Cost (No Synagis)

QALY (Synagis) – QALY (No Synagis)

• Current suggested “standards” for ICER :

– Accepted zone : $200,000

– Not generally accepted zone: > $200,000 / QALY

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0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

2,000,000

24 - 26 27 28 29 - 30 31 32

Gestational Age at Birth (Weeks)

Incr

emen

tal C

ost / Q

ALY

($ / QALY

)

Acceptable Zone =< $ 200,000 / QALY

$830,152/ QALY

$1,500,351 / QALY

$ 906,310/ QALY

$1,855,000/ QALY

With Drug Wastage

$685,720/ QALY

$1,268,679/ QALY

$657,780/ QALY

$1,481,965/ QALY

Without Drug Wastage

Effect of Gestational Age on ICER

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Why is the ICER so high?

• Substantial difference in costs, even without drug wastage • Very small difference in QALYs:

– No proven mortality benefit– No proven long-term quality of life improvement– Change in quality of life due to asthma is small: .03

• Treating many infants at low risk for hospitalization

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Large variation within GA in ICER

$0$500,000

$1,000,000$1,500,000$2,000,000$2,500,000$3,000,000$3,500,000

Month of Discharge

ICER

24-26 weeks27 weeks28 weeks29-30 weeks

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Improving the Recommendation’s Cost Effectiveness

• Simulations modifying the AAP guidelines• Assume no drug wastage• Restrict to 1st RSV season• Younger age cutoffs (Discharged Sept. through March)• Restrict to infants born 27 weeks GA or less if

discharged before RSV season; up to 30 weeks GA if discharged during RSV season

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ICER by GA and Month of Discharge with new Recommendation

$0$100,000$200,000$300,000$400,000$500,000$600,000

Jan.

Feb.

Mar. Apr.May

June

July

Aug.Sep

t.Oct.

Nov.Dec.

Month of Discharge

ICER

26 weeks27 weeks28 weeks30 weeks

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ICER by GA with New Recommendation

$0

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

26 weeks 27 weeks 28 weeks 29-30 weeks

Month of Discharge

ICER ICER

$103,053

$171,224

$216,830

$280,083

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Conclusion

• In our model for premature infants without CLD, incremental Cost / QALY:

– Was high for all gestational ages; Many ICER were over $1 million.

– Large amount of variation across months.• Simulations identified more cost-effective options.• Pursue strategies to minimize drug wastage.• AAP guidelines could be revisited to make them more

cost effective.

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Limitations

• Some costs were based on local estimates.• May have underestimated cost from family members missing

work due to infant hospitalized with RSV.• Unclear whether causal relationship between severe RSV

infection and asthma and other long-term health consequences; need for additional research.

• Decrease in quality of life due to asthma based on adults.

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University of Rochester Collaborators

• Department of Pediatrics, Division of Neonatology/Infectious Disease

Dr. Nahed El Hassan Dr. Timothy Stevens Dr. Caroline Hall

• Department of Community and Preventive Medicine

Dr. Andrew Dick