SCIOS NOVA’s PERGAMID NDA LACK OF RANDOMIZED TRIALS

Executive Summary

SCIOS NOVA's PERGAMID NDA LACK OF RANDOMIZED TRIALS was to have been a central issue to be discussed by FDA's Oncologic Drugs Advisory Committee at an aborted Nov. 17 meeting. Scios Nova's first product to be reviewed for approval by FDA, Pergamid (perfosfamide) is proposed as an ex vivo bone marrow purging agent in the treatment of acute myelocytic leukemia patients in complete remission who are undergoing high-dose chemotherapy with or without total body irradiation ("The Pink Sheet" Oct. 26, T&G-15). Nova filed its Pergamid NDA in April. The drug has been available via a Treatment IND since June 1991. The advisory committee meeting was canceled due to a water main break that shut down FDA's Parklawn Building headquarters in Rockville, Md. for one day. Both FDA and Scios Nova said that, as of Nov. 20, an alternate meeting date had not been set. Unlike several other FDA advisory committees, the oncologic committee does not schedule meetings far in advance, instead deciding on dates on an "as needed" basis. The introduction to the first question prepared for the Nov. 17 advisory committee meeting states that "there are no randomized clinical studies" to assess the safety and efficacy of Pergamid for its intended use. Part of another question asks the committee to discuss whether "randomized controlled trials are necessary to adequately evaluate the safety and efficacy of Pergamid." The advisory committee agenda contains six questions. Four questions describe specific Pergamid efficacy studies and ask whether each is "well-controlled" and demonstrates "the safety and efficacy of Pergamid." The fifth proposes for discussion possible control arms and endpoints that could be used in future Pergamid trials. The last question for the committee asks whether Pergamid is approvable and, if not, "what additional studies are necessary?" The first study described in the agenda is a unrandomized retrospective comparison of 189 patients undergoing autologous bone marrow transplant (ABMT) and receiving Pergamid purged marrow with 45 ABMT patients receiving unpurged marrow. The median event- free survival (EFS) time for the purged-marrow patients was 31 weeks versus 26 weeks for the unpurged group. Median survival time for purged versus unpurged patients was 45 weeks and 34 weeks, respectively. The agenda adds, however, that the purged group included "a statistically significant larger proportion of patients less than 19 years of age" and when these patients were excluded from the data analysis, differences in EFS and median survival "were markedly decreased." The unpurged group also had "significantly fewer bone marrow cells harvested and reinfused than the purged group," the agenda states. The second study outlined in the advisory committee agenda is a nonrandomized retrospective comparison of 130 Pergamid-treated patients to 47 patients receiving chemotherapy alone performed at the M. D. Anderson Cancer Center. Patients receiving Pergamid- purged marrow had a two-year survival rate of 46% versus 33% for those receiving chemotherapy alone. Median survival times were 78 weeks and 74 weeks, respectively. Of this study, the agenda says: "The study design does not permit comparison of the effect of bone marrow purging with no purging," "statistical analyses were not done," and "there was no comparative assessment of safety for this study." The advisory committee was also supposed to evaluate studies using mafosfamide, a chemical analog of Pergamid under development in Europe. The studies are retrospective comparisons of ABMT with mafosfamide versus transplants with unpurged marrow. The only prospective studies described on the agenda were sponsored by the National Cancer Institute and carried out by the Eastern Oncology Group and the Children's Cancer Study Group, comparing the use of Pergamid-purged ABMTs to allogeneic transplants. The agenda says that this trial design "does not permit assessment of the effect of purging." Scios Nova said it is currently conducting a prospective trial of Pergamid in which approximately 25 patients are enrolled.