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Economic Evaluations of Immunoprophylaxis in Infants at High Risk for Respiratory Syncytial Virus Shedding Light or Creating Confusion?  Terry
P. Klassen, MD, MSc, FRCPC GREAT ADVANCES in pediatrics have arisen from the discovery of new drugs designed to treat diseases that may cause death or severe morbidity in children. These discoveries most often arise from basic research and are brought to market by pharmaceutical companies at an estimated cost of $500 million per drug. 1 No one can dispute that much benefit to patients has emerged from these developments.Increasing emphasis is being placed on the need for decisions in health care to be evidence based. With the recognition that health care resources are limited, it has become equally important for new interventions to undergo economic evaluations. Without such examinations of the efficiency of new interventions, the costs of health care will escalate at an ever-faster rate. In many countries, costs for pharmaceutical agents are becoming the fastest-growing component in their health care budgets. Bronchiolitis is a disease that has frustrated pediatricians for many years because of its huge impact on the resources of our children's hospitals. However, few interventions have proven both safe and effective. In high-risk infants, bronchiolitis has a disproportional impact. Hence, it is even more critical to identify effective and efficient interventions. In light of this, strategies that can lessen the impact of this disease have great appeal. Three randomized controlled trials (RCTs), involving 2261 infants, have examined the effectiveness of immunoprophylaxis in high-risk infants; 2 of these trials involved respiratory syncytial virus immunoglobulin intravenous (RSV-IGIV),2, 3 and 1 trial involved palivizumab.4 The primary observed benefit has been the reduction of hospitalization burden. No significant benefit has been observed in reducing mortality. In this context, an economic evaluation may be useful in helping clinicians and health administrators decide whether to adopt a passive immunization strategy. Economic evaluations ask the basic question of whether a new intervention is worth adopting, based on estimates of costs and benefits. In a cost-minimization study, the benefits are assumed to be the same for all interventions; hence, only the costs are compared. For other types of analyses, the costs of the alternatives are identified, and the benefits are valued in natural units (cost-effectiveness analysis), quality of life (cost-utility analysis), or dollar amounts (cost-benefit analysis). Guidelines for economic evaluations have been established and published.5 Yet evidence exists that many economic evaluations of drugs fail to meet a minimum standard of quality. Hill et al6 examined 326 pharmacoeconomic analyses that had been submitted to the Australian Pharmaceutical Benefits Scheme. Of these analyses, 218 (67%) had significant problems, including comparative clinical efficacy, comparator issues, modeling issues, and calculation errors.6 Evans7 has argued that such guidelines may give the false illusion of scientific rigor, clothing such evaluations in an outward appearance of respectability, while the influence of the funding organization may still distort conclusions and recommendations. His premise is based on the fact that there are too many levels of subjectivity and choice with regard to methods in an economic evaluation. The influence of funding support on study conclusions has been shown in other areas of medicine. Stelfox et al8 found a strong relationship between authors' published positions on the safety of calcium-channel antagonists and their financial relationships with pharmaceutical manufacturers. Editors of the major medical journals have recognized the potential of financial interest to distort the results and conclusions of studies. In a joint editorial, editors called on investigators to state full disclosure and to create university-industry agreements that would ensure scientific independence and integrity.1 Governments and health care organizations require some process by which to make decisions regarding the adoption of new therapeutic agents. Therefore, the question remains, can such distortion be avoided when performing an economic evaluation? The study by Kamal-Bahl et al9 in the October 2002 issue of the ARCHIVES illustrates this challenge. The authors performed a systematic review of 12 economic evaluations examining the use of both RSV-IGIV and palivizumab. The results had estimates that ranged from cost savings to considerable incremental costs per hospitalization that were avoided with the use of either agent. Studies comparing the 2 agents reported mixed results about their relative cost-effectiveness. How would a decision maker come to a firm conclusion about the adoption of either agent with such conflicting evidence? Even more disturbing in their systematic review was that when they stratified the studies according to whether there was some form of funding from the manufacturer, 4 of the 4 studies with pharmaceutical support reported the possibility of cost-effectiveness or cost-savings with prophylaxis in the entire high-risk infant population, either in their point estimate or in their sensitivity analysis, vs 0 of the 8 studies without such funding (P = .002). It is somewhat astounding that from 3 RCTs, 12 economic evaluations have been spawned. In the area of new oncology drugs, Friedberg et al10 have previously demonstrated that pharmaceutical-sponsored economic evaluations were significantly less likely to report unfavorable results than those without such sponsorship. If economic evaluations are to play a key role in health care decision making, greater clarity is required. Rigorous RCTs designed with sufficient power to detect clinically important differences in clinically relevant outcomes must remain a cornerstone of such evaluations. The debate about RSV-IGIV and palivizumab would have significantly been clarified had even larger RCTs been conducted using mortality or markers of severe morbidity, outcomes other than health services utilizations. Economic evaluations must be methodologically sound and conducted by individuals with sufficient training and expertise to understand the nuances and complexities of economics. At the same time, there must be sufficient transparency for others to read, understand, and potentially replicate the study. At the very minimum, disclosure of sponsorship should be mandatory, but it is probably not fully sufficient to guard against bias. The systematic review of economic evaluations of palivizumab and RSV-IGIV by Kamal-Bahl et al would suggest that pharmaceutical sponsorship per se would severely undermine any conclusions reached. As Lewis has stated, "Some bargains are Faustian and some horses are Trojan. Dance carefully with the porcupine, and know in advance the price of intimacy."11(p785)
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© 2002 American Medical Association. All rights reserved. |
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