- Email: [email protected]
Should respiratory care in preterm infants include prophylaxis against respiratory syncytial virus? The case against
Paediatric Respiratory Reviews 14 (2013) 128–129
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Pro-Con Debate
Should respiratory care in preterm infants include prophylaxis against respiratory syncytial virus? The case against David Isaacs * Department of Infectious Diseases & Microbiology, Children’s Hospital at Westmead, Westmead, NSW, 2145, Australia and Division of Child Health, University of Sydney, NSW, 2006
A R T I C L E I N F O
S U M M A R Y
Keywords: Cost-effectiveness Quality-adjusted life years Indication creep
Preterm infants are at increased risk of severe respiratory syncytial virus (RSV) infection. The monoclonal antibody palivizumab reduces the frequency of preterm infants being admitted to hospital with RSV infection. However, palivizumab is expensive, has to be given by intramuscular injection monthly for 5 months and has to be given prophylactically to 17 preterm children to prevent one hospital admission with RSV and to 59 children to prevent one intensive care admission. Cost-effectiveness analyses have not shown that palivizumab is cost-effective for any sub-group with sufficient certainty to recommend its public funding. Palivizumab will only be cost-effective if the price drops. Paying for palivizumab is an opportunity cost; the money could be spent better on other more cost-effective health care interventions. Palivizumab should not be prescribed for any preterm child unless it can be shown to be cost-effective in that situation. Crown Copyright ß 2013 Published by Elsevier Ltd. All rights reserved.
Preterm infants are at increased risk of hospitalisation from severe respiratory syncytial virus (RSV) infection in the winter months in their first year of life, particularly if they have chronic lung disease, and over 95% of children will be infected with RSV before two years of age.1 Prevention is better than cure and is the ideal. Prophylaxis against respiratory syncytial virus (RSV) infection can currently only be achieved through passive immunity using the monoclonal antibody palivizumab. A new monoclonal antibody called motivizumab has been developed, but although there were hopes that motivizumab might be superior to palivizumab, early studies suggest motivizumab has equivalent but not superior efficacy.2 There is no effective vaccine and RSV immunoglobulin is no longer recommended.3 There is strong evidence that palivizumab is effective. In a large randomised controlled trial of 1002 infants who received prophylactic palivizumab and 500 controls, palivizumab reduced the rate of hospitalisation of high-risk infants due to RSV infection from 10.6% to 4.8%.4 It should be noted that the authors of the study and the sponsor of palivizumab report these data as showing that palivizumab reduces the risk of hospitalisation by 55%. It is true that the relative reduction (from 10.6% to 4.8%) is 55%. However, it is more pertinent when reporting efficacy to report the absolute reduction in hospital admissions. Palivizumab reduced the absolute risk of admission by 5.8% (10.6%-4.8%), which means it
* Department of Infectious Diseases & Microbiology, Children’s Hospital at Westmead, Westmead, NSW, 2145, Australia. E-mail address: [email protected].
is necessary to give prophylaxis to about 17 children to prevent one child being admitted to hospital with RSV infection. Since prophylaxis involves monthly injections for 5 months with an extremely expensive drug, the overall cost to prevent one hospital admission is very high. Furthermore, the absolute reduction in children with chronic lung disease was 4.9%, lower than for preterm children without chronic lung disease, and the number needed to treat (NNT) with prophylactic palivizumab to prevent one admission of a child with chronic lung disease was 20.3 Palivizumab reduced the incidence of admission to intensive care significantly from 3.0% to 1.3% (absolute reduction 1.7%, NNT to prevent one intensive care admission = 59).4 Four children (0.4%) in the palivizumab arm died and 5 controls (1.0%), a difference that was not statistically significant.4 If prophylaxis works, why should we not all use it? One reason would be if it costs too much and the money could be spent better on an alternative health-care intervention. This is the concept of costeffectiveness. In bygone days, Dr Fitzgerald and I satirised costeffectiveness analyses, since they appeared to rely too heavily on woolly estimates of indirect costs, such as the time parents take off work when their child is ill, and reported that Christmas was not cost-effective.5 However, cost-effectiveness analyses performed by expert committees which advise Government on the costeffectiveness of drugs in Australia (the Pharmaceutical Benefits Advisory Committee or PBAC) and the United Kingdom (the National Institute for Health and Clinical Excellence or NICE) do not include indirect costs because Quality-Adjusted Life Years (QALYs) already capture productivity gains. QALYs are used to assess the costeffectiveness of drugs and compare the effectiveness of different
1526-0542/$ – see front matter . Crown Copyright ß 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2012.12.006
D. Isaacs / Paediatric Respiratory Reviews 14 (2013) 128–129
drugs for different conditions. The cost per QALY saved is the average cost to prolong a patient’s life in good health by one year. For a drug that improves health but does not save lives, the QALY can be assessed by asking a sample of the public how much of their life they would be prepared to sacrifice to have good health rather than live with that particular disease state. The greater the cost per QALY, the less likely that the PBAC or NICE will recommend funding. Although the value and reliability of QALYs can be criticised, the bio-ethicist Peter Singer has used the argument that Winston Churchill used to defend democracy: ‘‘the QALY is the worst method of allocating health care, except for all the rest’’.6 If a drug or vaccine is not cost-effective for a population, there are two alternatives. One is that the company drops its price. The other is to identify sub-populations at increased risk for whom the intervention is cost-effective. For example, hepatitis A vaccine is funded in Australia only for Aboriginal children, who have a higher incidence than non-Aboriginal children, so that the vaccine is only cost-effective for Aboriginal children.7 Even if it was proved that palivizumab did save lives, we are not morally obliged to use palivizumab, despite what many people argue. Although clinicians and parent support groups might argue that it is immoral to let children die (‘‘What price do you put on the value of a human life?’’ You can hear them cry), the truth is that cost has to be an issue when allocating limited health-care resources. Costly interventions are an opportunity cost which might be spent on other competing health care interventions which save lives or prolong lives or improve quality-of-life. For example the cost of widespread use of prophylactic palivizumab in a health-care service might mean there was no money left to fund human papilloma virus vaccine to prevent cervical cancer. Peter Singer has described how in the USA health care rationing is demonised and how it has been portrayed as denying life-saving treatments.6 However, Singer argues cogently that the USA needs to ration health care according to competing priorities to prevent the ever-increasing health care costs which will eventually be unaffordable.6 The cost-effectiveness of palivizumab prophylaxis depends on the risk of acquiring RSV infection (which will vary depending on factors such as exposure to siblings and other children with RSV and also varies with the season), the severity of infection (which increases with increasing prematurity and with pre-existing chronic lung disease) and the costs of the drug and its administration.8 Is palivizumab cost-effective? Repeated studies have suggested that at its current price it is not cost-effective for the general paediatric population.8 However, some studies purport to show that palivizumab may be cost-effective for certain high-risk subgroups.8 A meta-analysis of cost-effectiveness studies examined high risk sub-groups.9 This meta-analysis found that palivizumab might be cost-effective for children with chronic lung disease who were born at 28 weeks gestation or less, who were <6 months old but no older than 21 months at the start of the RSV season.9 However, the authors concluded that the poor quality of the studies meant that there was considerable uncertainty in the calculations and that the true cost-effectiveness may vary considerably from their estimates.9 When Governments decide on whether or not to fund a drug, they are very keen to avoid possible blow-outs of cost, and such blow-outs are far more likely when there is uncertainty about cost-effectiveness. For this reason, the PBAC and NICE do not recommend funding drugs when the estimate of the cost per QALY is uncertain. While it has been stated that many countries have recommended the use of palivizumab, often on the advice of expert
129
advisory committees, it is important to consider two things. Firstly, does the country have a national health service which pays for the drug? It is easy to recommend the use of a drug you do not have to pay for. Secondly, if palivizumab is recommended, is this on the basis of cost-effectiveness? In Australia, the PBAC advises the Government whether or not a drug is cost-effective and the Government cannot commit national funds to the drug unless the PBAC says the drug is cost-effective. The PBAC has considered applications for palivizumab for high-risk children on a number of occasions, and has repeatedly found that palivizumab is not costeffective, even for those sub-groups at highest risk of severe RSV infection. The pharmaceutical company marketing palivizumab has been given the option to reduce their price each time, but has repeatedly declined to do so. In the UK, palivizumab was considered by a working party for the national immunisation committee, the Joint Committee on Vaccination and Immunisation (JCVI) but not by NICE. This working party considered effectiveness but not cost-effectiveness, and the JCVI did not consider cost-effectiveness when recommending that palivizumab should be funded for some high-risk infants and children.8 It is estimated that 1.1% of all UK children are eligible to receive palivizumab each year.8 The pharmaceutical company marketing palivizumab does so by appointing opinion leaders to ‘‘advisory committees’’ and by trying to persuade clinicians to broaden the use of palivizumab without generating new evidence of cost-effectiveness. I have described this policy as ‘‘indication creep’’.10,11 In my view, we should not use palivizumab for any high-risk group unless its use can be shown to be cost-effective. This either means generating convincing evidence that palivizumab is cost-effective, which is unlikely since further large randomised trials are unlikely to be funded, or else the pharmaceutical company needs to drop their price. We have a moral obligation to use drugs responsibly and not to waste public money on health care interventions that are not cost-effective.
References 1. Szabo SM, Gooch KL, Korol EE, Bradt P, Vo P, Levy AR. Respiratory distress syndrome at birth is a risk factor for hospitalization for lower respiratory tract infections in infancy. Pediatr Infect Dis J 2012 Sep 17 [Epub ahead of print]. 2. Carbonell-Estrany X, Simo˜es EA, Dagan R, et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a non-inferiority trial. Pediatrics 2010;125:e35–51. 3. Wang EEL, Tang NK. Immunoglobulin for preventing respiratory syncytial virus infection. The Cochrane Database of Systematic Reviews )1999;(Issue 3). CD001725. 4. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531–7. 5. Isaacs D, Fitzgerald D. A seasonal cost-effectiveness analysis: the last Noel? BMJ 2002;325:1426. 6. Singer P. Why we must ration health care. New York Times, July 15, 2009. http:// www.nytimes.com/2009/07/19/magazine/19healthcare-t.html (accessed Nov 11th, 2012). 7. Australian Government Department of Health and Ageing. The Australian Immunisation Handbook. 9th edition. Canberra, Australian Government Publishing, 2008. http://www.health.gov.au/internet/immunise/publishing.nsf/ Content/Handbook-home (accessed November 11th, 2012). 8. Teale A, Deshpande S, Burls A. Palivizumab and the importance of cost-effectiveness. BMJ 2009;338:1474–6. 9. Wang D, Bayliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. Health Technol Assess 2011;15:iii–v. 1–124. 10. Isaacs D. Palivizumab. An example of indication creep. BMJ 2009;339:b2724. 11. Fitzgerald D, Isaacs D, Tobin B. Palivizumab: a debate about public funding. J Paed Child Health 2012;48:373–7.
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Pro-Con Debate
Should respiratory care in preterm infants include prophylaxis against respiratory syncytial virus? The case against David Isaacs * Department of Infectious Diseases & Microbiology, Children’s Hospital at Westmead, Westmead, NSW, 2145, Australia and Division of Child Health, University of Sydney, NSW, 2006
A R T I C L E I N F O
S U M M A R Y
Keywords: Cost-effectiveness Quality-adjusted life years Indication creep
Preterm infants are at increased risk of severe respiratory syncytial virus (RSV) infection. The monoclonal antibody palivizumab reduces the frequency of preterm infants being admitted to hospital with RSV infection. However, palivizumab is expensive, has to be given by intramuscular injection monthly for 5 months and has to be given prophylactically to 17 preterm children to prevent one hospital admission with RSV and to 59 children to prevent one intensive care admission. Cost-effectiveness analyses have not shown that palivizumab is cost-effective for any sub-group with sufficient certainty to recommend its public funding. Palivizumab will only be cost-effective if the price drops. Paying for palivizumab is an opportunity cost; the money could be spent better on other more cost-effective health care interventions. Palivizumab should not be prescribed for any preterm child unless it can be shown to be cost-effective in that situation. Crown Copyright ß 2013 Published by Elsevier Ltd. All rights reserved.
Preterm infants are at increased risk of hospitalisation from severe respiratory syncytial virus (RSV) infection in the winter months in their first year of life, particularly if they have chronic lung disease, and over 95% of children will be infected with RSV before two years of age.1 Prevention is better than cure and is the ideal. Prophylaxis against respiratory syncytial virus (RSV) infection can currently only be achieved through passive immunity using the monoclonal antibody palivizumab. A new monoclonal antibody called motivizumab has been developed, but although there were hopes that motivizumab might be superior to palivizumab, early studies suggest motivizumab has equivalent but not superior efficacy.2 There is no effective vaccine and RSV immunoglobulin is no longer recommended.3 There is strong evidence that palivizumab is effective. In a large randomised controlled trial of 1002 infants who received prophylactic palivizumab and 500 controls, palivizumab reduced the rate of hospitalisation of high-risk infants due to RSV infection from 10.6% to 4.8%.4 It should be noted that the authors of the study and the sponsor of palivizumab report these data as showing that palivizumab reduces the risk of hospitalisation by 55%. It is true that the relative reduction (from 10.6% to 4.8%) is 55%. However, it is more pertinent when reporting efficacy to report the absolute reduction in hospital admissions. Palivizumab reduced the absolute risk of admission by 5.8% (10.6%-4.8%), which means it
* Department of Infectious Diseases & Microbiology, Children’s Hospital at Westmead, Westmead, NSW, 2145, Australia. E-mail address: [email protected].
is necessary to give prophylaxis to about 17 children to prevent one child being admitted to hospital with RSV infection. Since prophylaxis involves monthly injections for 5 months with an extremely expensive drug, the overall cost to prevent one hospital admission is very high. Furthermore, the absolute reduction in children with chronic lung disease was 4.9%, lower than for preterm children without chronic lung disease, and the number needed to treat (NNT) with prophylactic palivizumab to prevent one admission of a child with chronic lung disease was 20.3 Palivizumab reduced the incidence of admission to intensive care significantly from 3.0% to 1.3% (absolute reduction 1.7%, NNT to prevent one intensive care admission = 59).4 Four children (0.4%) in the palivizumab arm died and 5 controls (1.0%), a difference that was not statistically significant.4 If prophylaxis works, why should we not all use it? One reason would be if it costs too much and the money could be spent better on an alternative health-care intervention. This is the concept of costeffectiveness. In bygone days, Dr Fitzgerald and I satirised costeffectiveness analyses, since they appeared to rely too heavily on woolly estimates of indirect costs, such as the time parents take off work when their child is ill, and reported that Christmas was not cost-effective.5 However, cost-effectiveness analyses performed by expert committees which advise Government on the costeffectiveness of drugs in Australia (the Pharmaceutical Benefits Advisory Committee or PBAC) and the United Kingdom (the National Institute for Health and Clinical Excellence or NICE) do not include indirect costs because Quality-Adjusted Life Years (QALYs) already capture productivity gains. QALYs are used to assess the costeffectiveness of drugs and compare the effectiveness of different
1526-0542/$ – see front matter . Crown Copyright ß 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2012.12.006
D. Isaacs / Paediatric Respiratory Reviews 14 (2013) 128–129
drugs for different conditions. The cost per QALY saved is the average cost to prolong a patient’s life in good health by one year. For a drug that improves health but does not save lives, the QALY can be assessed by asking a sample of the public how much of their life they would be prepared to sacrifice to have good health rather than live with that particular disease state. The greater the cost per QALY, the less likely that the PBAC or NICE will recommend funding. Although the value and reliability of QALYs can be criticised, the bio-ethicist Peter Singer has used the argument that Winston Churchill used to defend democracy: ‘‘the QALY is the worst method of allocating health care, except for all the rest’’.6 If a drug or vaccine is not cost-effective for a population, there are two alternatives. One is that the company drops its price. The other is to identify sub-populations at increased risk for whom the intervention is cost-effective. For example, hepatitis A vaccine is funded in Australia only for Aboriginal children, who have a higher incidence than non-Aboriginal children, so that the vaccine is only cost-effective for Aboriginal children.7 Even if it was proved that palivizumab did save lives, we are not morally obliged to use palivizumab, despite what many people argue. Although clinicians and parent support groups might argue that it is immoral to let children die (‘‘What price do you put on the value of a human life?’’ You can hear them cry), the truth is that cost has to be an issue when allocating limited health-care resources. Costly interventions are an opportunity cost which might be spent on other competing health care interventions which save lives or prolong lives or improve quality-of-life. For example the cost of widespread use of prophylactic palivizumab in a health-care service might mean there was no money left to fund human papilloma virus vaccine to prevent cervical cancer. Peter Singer has described how in the USA health care rationing is demonised and how it has been portrayed as denying life-saving treatments.6 However, Singer argues cogently that the USA needs to ration health care according to competing priorities to prevent the ever-increasing health care costs which will eventually be unaffordable.6 The cost-effectiveness of palivizumab prophylaxis depends on the risk of acquiring RSV infection (which will vary depending on factors such as exposure to siblings and other children with RSV and also varies with the season), the severity of infection (which increases with increasing prematurity and with pre-existing chronic lung disease) and the costs of the drug and its administration.8 Is palivizumab cost-effective? Repeated studies have suggested that at its current price it is not cost-effective for the general paediatric population.8 However, some studies purport to show that palivizumab may be cost-effective for certain high-risk subgroups.8 A meta-analysis of cost-effectiveness studies examined high risk sub-groups.9 This meta-analysis found that palivizumab might be cost-effective for children with chronic lung disease who were born at 28 weeks gestation or less, who were <6 months old but no older than 21 months at the start of the RSV season.9 However, the authors concluded that the poor quality of the studies meant that there was considerable uncertainty in the calculations and that the true cost-effectiveness may vary considerably from their estimates.9 When Governments decide on whether or not to fund a drug, they are very keen to avoid possible blow-outs of cost, and such blow-outs are far more likely when there is uncertainty about cost-effectiveness. For this reason, the PBAC and NICE do not recommend funding drugs when the estimate of the cost per QALY is uncertain. While it has been stated that many countries have recommended the use of palivizumab, often on the advice of expert
129
advisory committees, it is important to consider two things. Firstly, does the country have a national health service which pays for the drug? It is easy to recommend the use of a drug you do not have to pay for. Secondly, if palivizumab is recommended, is this on the basis of cost-effectiveness? In Australia, the PBAC advises the Government whether or not a drug is cost-effective and the Government cannot commit national funds to the drug unless the PBAC says the drug is cost-effective. The PBAC has considered applications for palivizumab for high-risk children on a number of occasions, and has repeatedly found that palivizumab is not costeffective, even for those sub-groups at highest risk of severe RSV infection. The pharmaceutical company marketing palivizumab has been given the option to reduce their price each time, but has repeatedly declined to do so. In the UK, palivizumab was considered by a working party for the national immunisation committee, the Joint Committee on Vaccination and Immunisation (JCVI) but not by NICE. This working party considered effectiveness but not cost-effectiveness, and the JCVI did not consider cost-effectiveness when recommending that palivizumab should be funded for some high-risk infants and children.8 It is estimated that 1.1% of all UK children are eligible to receive palivizumab each year.8 The pharmaceutical company marketing palivizumab does so by appointing opinion leaders to ‘‘advisory committees’’ and by trying to persuade clinicians to broaden the use of palivizumab without generating new evidence of cost-effectiveness. I have described this policy as ‘‘indication creep’’.10,11 In my view, we should not use palivizumab for any high-risk group unless its use can be shown to be cost-effective. This either means generating convincing evidence that palivizumab is cost-effective, which is unlikely since further large randomised trials are unlikely to be funded, or else the pharmaceutical company needs to drop their price. We have a moral obligation to use drugs responsibly and not to waste public money on health care interventions that are not cost-effective.
References 1. Szabo SM, Gooch KL, Korol EE, Bradt P, Vo P, Levy AR. Respiratory distress syndrome at birth is a risk factor for hospitalization for lower respiratory tract infections in infancy. Pediatr Infect Dis J 2012 Sep 17 [Epub ahead of print]. 2. Carbonell-Estrany X, Simo˜es EA, Dagan R, et al. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a non-inferiority trial. Pediatrics 2010;125:e35–51. 3. Wang EEL, Tang NK. Immunoglobulin for preventing respiratory syncytial virus infection. The Cochrane Database of Systematic Reviews )1999;(Issue 3). CD001725. 4. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531–7. 5. Isaacs D, Fitzgerald D. A seasonal cost-effectiveness analysis: the last Noel? BMJ 2002;325:1426. 6. Singer P. Why we must ration health care. New York Times, July 15, 2009. http:// www.nytimes.com/2009/07/19/magazine/19healthcare-t.html (accessed Nov 11th, 2012). 7. Australian Government Department of Health and Ageing. The Australian Immunisation Handbook. 9th edition. Canberra, Australian Government Publishing, 2008. http://www.health.gov.au/internet/immunise/publishing.nsf/ Content/Handbook-home (accessed November 11th, 2012). 8. Teale A, Deshpande S, Burls A. Palivizumab and the importance of cost-effectiveness. BMJ 2009;338:1474–6. 9. Wang D, Bayliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. Health Technol Assess 2011;15:iii–v. 1–124. 10. Isaacs D. Palivizumab. An example of indication creep. BMJ 2009;339:b2724. 11. Fitzgerald D, Isaacs D, Tobin B. Palivizumab: a debate about public funding. J Paed Child Health 2012;48:373–7.