PEDIATRICS Vol. 106 No. 5 November 2000, pp. 1168-1169

Palivizumab (Synagis): Counting "Costs" and Values

To the Editor.

The continuing reports, letters, and pharmacoeconomic analyses concerning the use of expensive respiratory syncytial virus (RSV) prophylaxis regimens for neonatal intensive care unit (NICU) graduates mark what appears to be a shift in decisional processes for clinicians.^1-3 The consideration of cost, although not new in medical or pediatric decision-making, must be approached with care as decisions to provide or withhold therapies or prophylactic interventions for certain patient populations are made. In attempting to assess the costs of a proposed therapy or prophylactic regimen, and make decisions accordingly, one must recognize the attendant implied values of all parties affected by such decisions toward either the intervention or the outcome. Values are inherently subjective and will be perceived differently by different groups ... eg, patients, families of patients, the general public in a public health sense, taxpayers, physicians, hospital administrators, private insurance and payer groups, and industry. "Cost" analyses must be inclusive of more than simple pharmacoeconomic constructs that are currently available.

"Value" analyses should include considerations for:

1. Medical-physiologic aspects of the regimen; eg, "Does it work?"
2. Pharmacoeconomic perceptions of institutions, hospitals, and payer groups.
3. Personal or parental/family values both individually and more corporately; eg, a social utility perspective that should include the voices of parents of at-risk infants. This includes consideration of time and expenses borne by parents, employers, and daycare providers for physician office visits, emergency department visits, hospitalization, and treatments, as well as residual concerns about the infant's health.
4. A broader and somewhat more long-term societal view that might consider:
   a) years of life saved/lost
   b)  productive versus debilitated life (eg, residual pulmonary morbidity, either acute or long-term)
5. The societal value assumed already in treating premature infants and preserving their health (eg, the societal expectation for the availability and optimal outcome from NICUs, and the investment society makes in this broadly as well as the costs already borne by families, payers, and society to get a premature infant to the point of discharge).
6. The relative value of RSV prophylaxis as a fraction of total NICU economic and resource costs (realizing that for many premature infants hospitalization charges have been in the hundreds of thousands of dollars).

Furthermore, pharmacoeconomic analyses should be projected forward from the point of NICU discharge and consideration for RSV prophylaxis to include the continued post-NICU discharge investment in infants during the first 12 months of life such as: a) percent of rehospitalization; b) number/costs of visits to pediatrician's offices or emergency departments in the first year of life (bronchopulmonary dysplasia-related, and otherwise); c) relative costs of RSV prophylaxis to continued investment in post-NICU care, such as any effect on a reduction in office/emergency department visits, ward/ICU hospitalization, and oxygen or ventilator days; reduced post-RSV infection care (such as office/emergency department visits for wheezing and reactive airways disease and consequent therapies)⁴; reduced numbers of sick days and their effect on parents' and siblings' emotional state, employment, daycare arrangements, and costs.

Recent history attests to the consideration of social utility in a number of decisions for providing or withholding certain therapies. Blood products are often withheld from Jehovah's Witnesses and recombinant erythropoietin has been suggested as a preferred alternative therapy for some infants of Jehovah's Witness parents who might only require a small transfusion. In the AAP recommendations for the use of varicella vaccine, deference is given to the social impact of infection; recommendations for vaccination to avoid these social "costs" has resulted in an essentially universal vaccination program in the United States.⁵ No published data exist, however, to substantiate that there has been either a reduction in the total numbers of varicella cases, hospitalizations, or deaths in the 5 years since the vaccine was approved. The economic costs of this vaccination program have not been inconsiderable, given an estimated charge of $30 to $40 per vaccine when applied to the more than 4 million infants born in the United States each year.

In attempting to arrive at consistency in clinical decision-making, issues of strict economic cost cannot overshadow a more thorough evaluation of value. In the recent RSV prophylaxis literature, the only costs being considered are those of the hospital or payer groups (private and public). Although a recent report by Joffe et al² gives some consideration to a hypothetical cohort of premature patients, no published trials have tabulated actual costs to families for RSV disease-related care or considered the costs to parents of potential recipients of RSV prophylaxis who were either not informed about the availability of the regimen or denied the drug. Such costs might be considered emotional or perceptual (because parents know about RSV and dread it), or very real (because they visit the physician's office with every cough and runny nose their formerly premature infant gets; or worse, have lost a child to RSV). Simple pharmacoeconomic commentaries are not enough. It is people that pediatricians treat, and very human values become much more significant in the decisional process (remember "shared decision-making"). It should not be the place of physicians or payer groups alone to assume the perogative to deny some babies RSV prophylaxis because of available pharmacoeconomic cost data. Unilateral decisions of such a nature amount to rationing, which is not uncommonly practiced in somewhat inconsistent manners ... such that someone, or some group of patients from some payer groups, will not be justly represented.

In the issue of RSV prophylaxis for NICU graduates, pediatricians might be better off wearing the hat of a child advocate than a gatekeeper.

Brian S. Carter
Clarksville, TN 37043

REFERENCES

1. Connor EM, Carlin D, Top FH, Weisman LE Questions about palivizumab (Synagis). Pediatrics. 1999; 103:535-536
2. Joffe S, Ray GT, Escobar GJ, Black SB, Lieu TA Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics. 1999; 104:419-427 [Abstract/Free Full Text]
3. Moler FW RSV immune globulin prophylaxis: is an ounce of prevention worth a pound of cure? Pediatrics. 1999; 104:559-560 [Free Full Text]
4. Stein RT, Sherrill D, Morgan WJ, Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999; 354:541-528 [CrossRef][Medline]
5. American Academy of Pediatrics, Committee on Infectious Diseases Policy statement Recommendations for the use of live attenuated varicella vaccine. Pediatrics. 1995; 95:791-796 [Abstract/Free Full Text]

In Reply.

The letter by Dr Carter lists several emotional issues pediatricians must face when they decide whether to recommend immune globulin prophylaxis for RSV in high-risk infants. Recent publications related to RSV-IGIV and palivizumab have suggested that the costs of these products may not be justified based on the hospital outcomes prevented.^1-3 At this time, immune globulin prophylaxis for RSV has not yet been established to affect severe outcomes like need for mechanical ventilation or mortality. Beneficial effects of development of future chronic lung disease are also not known. What is known at this time is simply that immune globulin products for RSV do not decrease the number of hospital admissions for uncomplicated RSV disease. Unfortunately, the additional costs to avoid a single uncomplicated hospitalization for RSV may be in the range of an order of magnitude greater than the costs of hospitalization avoided.⁴ (We previously estimated it would cost over $75,000 to prevent an uncomplicated RSV hospitalization. This was based on an assumption that just over 17 patients would require treatment to avoid 1 hospitalization (number needed to treat [NNT] = 17) and cost for 5 monthly intramuscular (IM) injections of palivizumab would be $4,500 per season. The cost to avoid a single day of hospitalization was estimated to be just over $17,000, and would additionally require 19 IM injections and up to 19 clinic visits). Because there exist limited and finite resources for health care in the United States, widespread prevention of RSV hospitalization by way of immune globulin prophylaxis must eventually result in fewer resources for other deserving patient groupsless money for human immunodeficiency virus prevention and treatment, less money for treatment of children with mental and physical disabilities as a result of prematurity or other conditions, fewer resources for accident prevention, etc. The Evidence-Based Medicine Working Group has provided useful guidelines that may be used to estimate cost-effectiveness of therapies so that practitioners may be guided in their decisions.⁵ One of the RSV immune globulin cost-effectiveness studies used such methodology and was additionally reviewed by members of this expert group.¹ A recent publication by Hall et al⁶ comments on the need to narrow the published guidelines for RSV prophylaxis and describes a method to assist in the selection of patients to receive immune globulin prophylaxis.

Presently, it is estimated that over 40 million Americans do not have health insurance. It is likely that most of the individuals in this group are in this predicament because of the inability to pay escalating health care premium costs and nonqualification for public-sponsored health insurance programs. These individuals may be expected to worry no less about the health of their family members and the impact on their family's financial status of any hospitalization not covered by health insurance than parents of premature infants at risk of RSV hospitalization. For such individuals, new therapies that have relatively small beneficial effects at very high cost have the potential to make health care premiums even more out of reach for their families, and additionally may result in families currently with health care insurance to no longer be able to afford future coverage. On the other hand, each new therapy that results in the net reduction of health care costs for society should make health care more affordable to more currently uninsured individuals. Unless new information becomes available, it appears at this time that RSV immune globulin products fit into the former rather than latter category. The cost of RSV prophylaxis for a single infant would likely cover the majority of health insurance premiums of a family of 4 for an entire year. I believe most pediatricians, families, third-party payers and others would agreeif given the choice of either 1) health insurance for a family of 4 for 1 year or 2) RSV prophylaxis for a single infant for 1 yearthat health insurance coverage would be the overwhelming choice.

In the prior commentary,⁷ it was suggested that potentially far less costly strategies such as formal RSV educational programs should be examined and compared with active prophylaxis, as there appeared to potentially exist a strong educational effect in the prior immune globulin randomized clinical trials. It is possible that the effects of a well-constructed educational program may reduce RSV hospitalization greater than the effect of immune globulin prophylaxis. It was also suggested that it may be time for expert committees and organizations such as the AAP Committee on Infectious Diseases and the Food and Drug Administration to influence pharmaceutical makers by means at their disposal to set pharmaceutical costs based on reasonable observed benefits resulting from their products. For example, a signed petition by many AAP members calling for a reduction in cost of RSV immune globulin therapies may carry a strong message to pharmaceutical makers and medical industry in general. In this author's opinion, such action would represent very strong advocacy for all children's health care needs in a more meaningful manner than simply putting pressure on third-party payers (by way of emotional pleas) to pay for marginal therapies that have small benefits at large cost. It would be far better to provide all children with basic health care coverage for therapies that have the greatest impact on their health (including cost-effectiveness considerations), rather than to provide coverage for a smaller subset of children for all therapies possible (including therapies with very high cost and limited benefits).

Frank W. Moler
Department of Pediatrics and Communicable Diseases
University of Michigan Medical School
Ann Arbor, MI 48109

REFERENCES

1. Robbins JM, Tilford JM, Jacobs RF, Wheeler JG, Gillespy SR, Schutze GE A number-needed-to-treat analysis of the use of respiratory syncytial virus immune globulin to prevent hospitalization. Arch Pediatr Adolesc Med. 1998; 152:358-366 [Abstract/Free Full Text]
2. O'Shea TM, Sevick MA, Givner LB Costs and benefits of respiratory syncytial virus immunoglobulin to prevent hospitalization for lower respiratory tract illness in very low birth weight infants. Pediatr Infect Dis J. 1998; 17:587-593 [CrossRef][Medline]
3. Joffe S, Ray GT, Escobar GJ, Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics. 1999; 104:419-427
4. Moler FW, Brown RW, Faix RG, Gilsdorf JR Comments on palivizumab (Synagis). Pediatrics. 1999; 103:495-497 [Free Full Text]
5. Users' Guide to the Medical Literature XIII. How to use an article on economic analysis of clinical practice. B. What are the results and will they help me in caring for my patients? JAMA. 1997; 277:1802-1806 [Abstract/Free Full Text]
6. Hall CB, Stevens TP, Swantz RJ, Sinkin RA, McBride JT Development of local guidelines for prevention of respiratory syncytial virus infections. Pediatr Infect Dis J. 1999; 18:850-853 [CrossRef][Medline]
7. Molder FW RSV immune globulin prophylaxis: is an ounce of prevention worth a pound of cure? Pediatrics. 1999; 104:559-560

In Reply.

We thank Dr Carter for reminding readers that cost alone is an inadequate basis for medical decision-making. Cost-effectiveness analysis (CEA) is not intended to be an impersonal, self-sufficient machine for making resource allocation decisions. Rather, CEA should be considered a tool for making the costs and benefits of a given intervention explicit. Decision-makers can then incorporate this information, along with the value of all parties affected by the decision, as they deliberate policy. As the Panel on Cost Effectiveness in Health Care and Medicine stated,

... Cost-effectiveness analysis provides valuable information about tradeoffs in the broad allocation of health resources, but other factors need to be considered as wellconcepts of fairness and justice that are not fully captured in the sums of QALYs (quality-adjusted life-years) or in the way costs are valued, benefits and costs outside the health sector, and practical questions of feasibility. Thus, although it is possible to use CEA in a mechanical way, it is often not appropriate to do so. CEA is not a complete decision-making process. The information it provides is, however, crucial to good decisions.¹

The panel further recommended that community values be incorporated into CEAs in the form of utilities.² However, utilities are uncommonly incorporated into pediatric analyses because measuring them generally requires face-to-face interviews using specialized methods. Ideally, if research funding allows, utilities should be assessed. When utilities for relevant health outcomes are not available, the users of CEAs need to make implicit judgments about the relative values of the health benefits versus the dollars expended for a health care intervention.

Finally, no CEA can include all possible costs and benefits. Items that are included should be linked by evidence to the intervention being studied. In general, we agree with Dr Carter that the long-term as well as short-term benefits of any intervention should be included in analyses. We considered including in our analysis possible benefits of RSV prophylaxis aside from hospitalization during the immediate season, but no evidence is available that prophylaxis is associated with any such long-term advantages.³ In such a case, it is more appropriate to follow the conservative course of not crediting the intervention with unproven benefits.

Steven Joffe
Pediatric Hematology/Oncology
Dana-Farber Cancer Institute
Boston, MA 02115

Tracy A. Lieu
Division of Ambulatory Care and Prevention
Harvard Pilgrim Health Care
Boston, MA 02215

REFERENCES

1. Russell LB, Siegel JE, Daniels N, Gold MR, Luce BR, Mandelblatt JS. Cost-effectiveness analysis as a guide to resource allocation in health: roles and limitations. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, ed. Cost Effectiveness in Health and Medicine. New York, NY: Oxford University Press; 1996:3-24
2. Gold MR, Patrick DL, Torrance GW, et al. Identifying and valuing outcomes. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York, NY: Oxford University Press; 1996:82-134
3. Joffe S, Ray GT, Escobar GJ, Black SB, Lieu TA Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants. Pediatrics. 1999; 104:419-427