Comments on Palivizumab (Synagis)

Caregivers and third-party payors need additional information from the Impact study1investigators to determine the appropriate use of palivizumab (Synagis) in select premature infants with increased risk of respiratory syncytial virus (RSV)-associated hospitalization. The primary outcome variable of hospitalization within 30 days of the last dose of palivizumab may have missed patients who actually became ill with RSV later in the epidemic under study. Could the investigators provide data on the incidence of RSV hospitalization beyond the 30-day post-palivizumab cut point for each group in the IMpact study? Although the published study design may have provided an adequate outcome to demonstrate drug efficacy for Food and Drug Administration approval, failure to consider RSV hospitalization later in the epidemic (beyond 30 days after the fifth dose of palivizumab) would likely result in a discrepancy in palivizumab's true effectiveness in actual clinical practice compared with its efficacy under ideal study conditions of the randomized clinical trial. In addition, under actual clinical practice conditions, one would not anticipate palivizumab to be as effective as described under efficacy study conditions for other reasons such as missing or untimely palivizumab injections. Furthermore, under the IMpact study conditions, the control group may have been exposed to RSV infection to an extent greater than had they not participated in the study. The general study conditions of the 139 centers where patients waited until injections were administered was not described, but if waiting rooms were crowded with many children and adults during RSV epidemics, excessive RSV exposure for the control patients may have occurred. For these and other reasons, the effectiveness of palivizumab in actual clinical practice is likely to be less than the IMpact efficacy study may indicate.The cost effectiveness of palivizumab is also a major issue for consideration. In the recently published IMpact study, palivizumab was demonstrated to have a 55% efficacy to prevent RSV hospitalization under conditions of the study. From a public health perspective, a 5.8% attributable risk reduction (ARR) in the incidence of RSV hospitalization resulted (10.6% control group −4.8% palivizumab group). This means that 17.2 patients would need receive the course of palivizumab to prevent one RSV hospitalization (number needed to treat [NNT]). With five doses (one dose = one vial) given annually per patient and an anticipated cost of approximately $900 per dose, the annual cost would be $4500 per patient or $450 000 per 100 patients treated. This results in an estimated total drug cost of over $77 000 ($450 000/5.8) to prevent a single RSV hospitalization. From a slightly different perspective, data from the IMpact study show that for every 100 patients treated, 26.2 fewer hospital days were observed (62.6 placebo − 36.4 palivizumab days). Therefore, the cost to avoid a single hospital day is approximately $17 000.Charges to third-party payors would be an estimated $1200 per vial (dose), resulting in a charge of $6000 per patient per epidemic and $600 000 for every 100 patients treated. Third-party payor charges would be approximately $104 000 to avoid a hospital admission and $23 000 to avoid a single day in the hospital. We estimate the cost of prophylaxis at our center to be more than 10 times greater than the actual cost of excess hospitalization in untreated patients. Thus, reduction in palivizumab cost to <$100 per vial (dose) would be required to approximate the cost-effective break point at our center. Unfortunately, no reduction or even trends toward decreased severe outcomes such as mortality or requirement for mechanical ventilation was observed in the IMpact study to offset the very high cost of palivizumab. Table 1 represents our best estimation of the (drug only) cost to prevent a single RSV hospitalization from diagnostic subgroup data described in the IMpact study and from MedImmune, Inc. Of note, in premature infants without bronchopulmonary dysplasia the incidence of RSV hospitalization in the control group was less in those born at gestational age <32 weeks compared with those born between 32 and 35 weeks.It is interesting and very informative to consider the hypothetical situation where palivizumab prophylaxis resulted in absolute protection with no hospitalizations or days in the hospital for each 100 patients treated. Even here the cost of prophylaxis would not seem to be justified. Under this hypothetical perfect protection scenario, (ARR 10.6% [10.6% − 0%] with NNT 9.4) the cost to avoid one hospital admission would be approximately $42 000 and cost to avoid one patient hospital day $7188 (62.6 days − 0 days). It should be noted that only direct drug costs have been examined. Drug administration costs with adjustment for 500 clinic visits and intramuscular (IM) injections were not considered. Inclusion of these costs would have resulted in even less favorable cost effectiveness for palivizumab prophylaxis. Finally, we should again note that efficacy data (IMpact study) rather than actual effectiveness data in actual clinical practice has been used. Commonly, therapies have greater effects under ideal study conditions than under average clinical practice conditions for reasons described earlier and others like use of therapies in patients dissimilar from those included in clinical trials.The IMpact study in conjunction with two previous RespiGam studies may provide a very important observation concerning the best method to prevent RSV infection currently.1,2 An enhanced educational process directed at prevention of exposure to RSV apparently has resulted in reduced RSV hospitalization in placebo groups from 20% (NIAID trial3 to 13.5% (RespiGam study4) and to 10.6% (IMpact study). When and if phase IV postmarketing studies are conducted, it will be extremely important to control for the effect of caregiver RSV education on clinical outcomes in treated and untreated groups. In retrospect, had a second control group been followed in the IMpact study, which received the usual existing RSV education and not received blinded IM therapy, the education effect could have been better assessed.At this time, the only generalizable information which to estimate palivizumab cost-effectiveness in actual clinical practice comes from the IMpact efficacy study where 139 centers from the United States, Canada, and the United Kingdom participated. From this large international study we now know that palivizumab reduces RSV hospital admissions and hospital days. It does not, however, decrease patient mortality or the need for mechanical ventilation. Therefore, the decision to use this product should be closely linked to its cost-effectiveness. We believe if the baseline incidence of RSV infection at an individual center is greater than that reported in the IMpact trial (10.6%), perhaps the first order of business should be to examine and improve the education process that is provided to families of discharged premature infants with and without lung disease from that center. For our center, additional evidence of improved patient outcome or reduced drug cost will be needed.See Letters to the Editor in this issue by Dr Eppes, Drs Lee and Robinson, and the response to these letters from Dr Connor, et al.