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Executive Summary

Burroughs Wellcome's Exosurf Pediatric and Abbott subsidiary Ross Labs' Survanta were both recommended for approval by FDA's Pulmonary-Allergy Drugs Advisory Committee at its July 23 meeting. The advisory committee unanimously agreed that Exosurf Pediatric (colfosceril palmitate) and Survanta (surfactant TA) should be approved for use in the prevention and treatment of respiratory distress syndrome in premature infants. Although the lung surfactants are similar in therapeutic action and will be indicated similarly, FDA indicated that there will be some differences between the two products' labeling. "These products are chemically different," FDA Office of Drug Evaluation I Deputy Director Paula Botstein pointed out. Exosurf is a synthetic surfactant, whereas Survanta is derived from bovine sources. Noting that the study designs for the products were different, Botstein said that "the labeling for the two drugs is different, [although] there are some common themes." The labeling will most likely differ in dosing, recommended weights of infants being treated prophylactically, and adverse reactions -- areas where the clinical experience from each drug differed. In all groups of infants, the committee thought that the benefits outweighed the adverse effects of the drugs as long as the risk of respiratory distress syndrome has been established. Both drugs have been available under Treatment INDs for close to a year. Approved for treatment use in July 1989, Exosurf has been administered to aproximately 9,000 infants out of the 40,000 to 50,000 who develop RDS every year. Under a Treatment IND granted in September 1989, about 3,000 infants have been treated with Survanta. Burroughs Wellcome's Walker Long, MD, presented data on 2,831 patients from four trials in which patients received Exosurf either for prophylaxis or as a rescue regimen. Exosurf reduced mortality at 28 days in a single dose prevention study by 33%. When three doses of Exosurf were given, mortality dropped an additional 29%. Exosurf given as a treatment regimen of two doses significantly reduced mortality by 44% in midsized babies of 700 to 1350 grams weight. The reduction in mortality at one year was 33% for infants weighing more than 1,350 grams; however, the mortality reduction in this group was not considered statistically significant. Deaths from respiratory distress syndrome (RDS) and severity of RDS were consistantly reduced in all of the Exosurf trials. However, the incidence of RDS was not reduced and in only the trial of larger infants was the number of days spent on a ventilator significantly reduced from 8.5 days in the control group to 6.3 days in the Exosurf group. Another endpoint, the reduction of bronchopulmonary dysplasia (BPD), was only significantly reduced in the large baby rescue trial, although there was a trend toward reduction of BPD in the other rescue trial. Adverse events with Exosurf included an increased incidence of apnea and a significant increase of pulmonary hemorrhage. Although apnea occurred in 40-70% of infants, those patients that developed apnea had a greater survival rate and a 50% reduction in the incidence of severe intraventricular hemorrhage. There was a two-fold increase in pulmonary hemorrhages in the Exosurf group. However, concomitant administration with indomethacin demonstrated a protective effect. One-year followup in over 1,000 infants showed that Exosurf-treated patients overall had equivalent mental and motor development scores to the untreated group. However, in the subgroup of babies weighing less than 750 grams at the time of treatment, there was a 20 point increase in median IQ score over that of the control group. Functional handicaps were about 30% in both groups, with severe functional handicaps occurring less in the Exosurf treated group, 16% compared to 19% in the control group. Ross Labs' Harry Gunkel, MD, presented results of Survanta data from 1,691 infants. Mortality was significantly reduced in a majority of the trials presented. In two multiple dose trials, where infants received one to four doses of the drug, mortality dropped from 28% in the control group to 15% in the Survanta group. Death due to RDS was also reduced in combined single dose prevention studies, where there were no deaths in the Survanta group and 6.2% deaths in the control group. Unlike the clinical experience with Exosurf, the incidence of RDS was significantly reduced by Survanta in all the trials, from 40.5% to 11.8% in the single dose trials, and from 63.5% to 27.6%, and 48.3% to 28.6% in two multiple dose studies. Pulmonary air leaks and pulmonary interstitial emphysema were also significantly reduced. Two adverse reactions of Survanta that caused some concern among committee members were an increase in post-treatment sepsis and a significant increase of intracranial hemorrhage. However, Gunkel observed that "despite the increased ICH in the Survanta treated group, there appears to be no apparent problem with neurologic followup at 6 months of age." Followup studies to assess the long-term incidence of these two events were suggested at the meeting by FDA consultant Allen Merritt, MD, University of California San Deigo. Six-month followup of the single dose studies show that there are "no neurologic differences between Survanta and the control group," Gunkel reported. A followup of patients in the multiple dose trials shows that there is more hydrocephalus and cerebral palsy in control patients at six months. Fewer Survanta patients require oxygen at six months, Gunkel noted; however, there was a 9% unexplained incidence of wheezing in the survanta group at the time of the six month exam. Following the success of Survanta in children, Ross recently began clinical trials in adults. Burroughs Wellcome is already in Phase II for the treatment of respiratory distress syndrome with Exosurf in adults. The incidence of RDS in adults is possibly greater than that in infants, about 40,000 to 60,000 per year. Adults often contract RDS following a trauma or sepsis.

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