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SCIOS NOVA’s PERGAMID: NO FURTHER TRIALS WILL BE FUNDED

Executive Summary

SCIOS NOVA's PERGAMID: NO FURTHER TRIALS WILL BE FUNDED by the company for the experimental bone marrow purging agent, Scios Nova said March 1 at a meeting of FDA's Oncology Drugs Advisory Committee. Scios Nova VP-Clinical and Regulatory Affairs Elliott Grossbard, MD, postulated that to show prospectively that Pergamid for the treatment of acute myelogenous leukemia "would prolong survival and decrease the rate of relapse would require a study of 235 patients in each of two arms." He added: "I can say with certainty that we will not -- we cannot -- devote the resources to a study of this size to a population of patients that numbers at best in the very, very low thousands." Grossbard's comments came shortly before the advisory committee recommended by unanimous vote that Pergamid (perfosfamide) should not be approved. The Pergamid NDA contained no data from randomized prospective trials ("The Pink Sheet" Nov. 23, 1992, T&G-3). The committee voted unanimously that none of the retrospective studies submitted by the company constituted "well- controlled clinical trials." Pergamid has been available under a treatment IND since June 1991 and had been distributed under an investigator's IND since 1982. Nova acquired the product in 1989, two years before merging with Scios. At the advisory committee meeting, Scios Nova Senior Director of Regulatory Affairs Steven Rochelle explained that the availability of Pergamid and other unapproved marrow purging compounds "compromised our ability to perform clinical studies of purged versus unpurged patients." Patients and their physicians are unwilling to enter a trial in which some patients will receive unpurged marrow, he indicated. In 15 months, Scios Nova's prospective trial comparing autologous bone marrow transplant (ABMT) with Pergamid purging to ABMT with no purging in AML patients has enrolled 25 patients at four centers. Due to the difficulty of performing trials for any purging agent in AML, no purging agent has been proven effective, Committee Chairman Charles Schiffer, MD, University of Maryland Cancer Center, indicated. "Although most people would intuit that bone marrow purging in autologous transplant in leukemia is of benefit, there isn't even proof of that." The one retrospective trial comparing outcomes for ABMT with Pergamid purging versus ABMT without purging showed some survival advantages in the Pergamid group, but the results were not statistically significant, FDA and the company said. Of the remaining studies, committee member Daniel Ihde, MD, National Cancer Institute, said: "Trials that compare autologous transplant to something else [such as allogeneic transplants or chemotherapy alone] are really hard to evaluate." FDA medical reviewer Anthony Murgo, MD, who presented FDA's analysis of the Pergamid NDA, said of all but one of the studies: "The biggest concern is that the data do not evaluate the role of purging per se." Another concern, Murgo said, was that recipients of Pergamid- purged marrow did show "highly significant" increases in time to bone marrow engraftment, increasing hospital stay and need for platelet and red blood cell transfusions. The advisory committee was scheduled to review the Pergamid NDA at a November meeting, which was canceled due to a water main break at FDA's Parklawn headquarters. Between the time of the canceled meeting and March 1, FDA notified Scios Nova that Pergamid was not approvable. At the beginning of the March 1 meeting, Scios Nova VP-Development Robert Griffith, MD, commented: "We were somewhat surprised to receive a non-approvable letter from the agency in January when your committee hadn't had the chance to review our safety and efficacy data." Rochelle said, "The agency, however, in this letter gave the committee the opportunity to express a different view." Grossbard said Scios Nova "will probably withdraw the treatment IND" because of the "regulatory burden of monitoring the distribution of the product, manufacturing the product and performing quality control and quality assurance." He added that "we have thought several times about withdrawing the NDA" and later said that Scios Nova is open to offers for rights to the drug. Committee member Paul Bunn, MD, University of Colorado Cancer Center, told Grossbard: "I'm not sure it's your responsibility [to perform further studies]." He suggested that FDA or the company publish the Pergamid data in hope "that someone will perform the needed studies." Addressing the lack of investigators and patients willing to perform trials comparing Pergamid-purged ABMTs and unpurged ABMTs, Schiffer said: "The whole thing is very distressing because this is a potentially extremely important compound in a potentially extremely important therapy." Several committee members asked if NCI could take a role in organizing a Pergamid trial. Grossbard said: "As recently as [Feb. 26] I was in touch with someone at NCI to see if they would be prepared to help." FDA Oncology Group Leader John Johnson, MD, said: "We have met with NCI on two occasions and they have said they are unable to help us, but we will continue to press them."
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