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Executive Summary

Bristol-Myers' ifosfamide (Ifex) should be approved for use in a combination chemotherapeutic regimen for third-line treatment of refractory testicular cancer, FDA's Oncologic Drugs Advisory Committee agreed at its April 19 meeting. The committee specified that the approval should be conditioned upon labeling the drug for use with mesna, which is under development by Adria as a protective agent for urinary-bladder toxicity associated with certain chemotherapeutics. In addition, the committee suggested that FDA review existing historical control data that was not included in the NDA submission prior to granting approval. Bristol-Myers submitted the ifosfamide NDA in December 1987. Ifosfamide and mesna are currently available for the treatment of refractory testicular cancer under a Treatment IND sponsored by the National Cancer Institute. FDA approved the Treatment IND in December ("The Pink Sheet" Jan. 4, p. 10). Adria's mesna is currently in Phase III study. A Bristol-Myers representative told the committee that an NDA submission was expected imminently. The committee based its approval recommendation on the results of a single, one-center study in 59 testicular cancer patients who had failed on at least two prior chemotherapeutic regimens. The patients received ifosfamide, cisplatin (Bristol-Myers' Platinol), and either etoposide (Bristol-Myers' VePesid) or vinblastine. Most of the patients also received mesna as a protective agent. The study, conducted at the Indiana University Hospital, used historical data on third-line treatment as a control. The principal investigator of the study, Lawrence Einhorn, MD, reported that at the time of the NDA submission, 15 of the 59 patients, or 25%, had achieved complete remission following administration of the ifosfamide regimen. "An additional eight patients had a disease free status [after receiving the regimen and subsequent] surgical extrapolation of residual localized disease -- resection of either teratoma or carcinoma," Einhorn reported. Currently 13 of the patients are still alive with a disease free status. The patients have been followed for a minimum of two years, with a disease free status. The patients have been followed for a minimum of two years, with a median follow-up of 143 weeks. "Two of these 13 patients," Einhorn noted, "have relapsed with surgically resectable teratoma, not carcinoma, and are presently disease free." In comparison, there have been no disease-free survivors in the historical control group of 65 patients who received cisplatin, etoposide or vinblastine, and one of six experimental drugs during a comparable time period. While acknowledging that the survival rates of the trial were impressive, committee members observed that the exact contribution of ifosfamide was difficult to determine because the ifosfamide-treated patients had more favorable performance status rating than patients in the historical control group. For example, committee member Thomas Fleming, PhD, University of Washington, commented that "there is clear-cut activity . . . but the issue is to what extent is ifosfamide accounting for that activity. The historical control data that was provided I think is very weak and contributes very little to addressing that issue." Because the historical data does not provide an equivalent control group, Fleming continued, "in essence were left with trying to assess what is the natural history [of the disease] -- to what extent we can expect that these patients who have failed second-line would in fact be receptive to third-line if they were administered similar treatment without the ifosfamide." To resolve the issue of ifosfamide's role in the success of the the 59 patient study, the advisory committee recommended that FDA review the results of a recent trial at Indiana University Hospital in which 18 refractory testicular cancer patients were given a third-line treatment of cisplatin and etoposide after relapsing from an initial response to salvage (second-line) treatment with cisplatin and etoposide. Echoing the remarks of other committee members, Fleming commented that the 18 patient study, which was not included in the NDA but was discussed by Einhorn, "seems to be the most relevant control group information we have." Fleming added: "I personally would like to see that data. I need to understand more about whether or not we have comparability of that group with the [NDA study]." Discussing results of the 18-patient study, Einhorn reported that "out of those 18 patients in this historical control retrospective analysis, only one is currently disease free. This particular patient achieved a complete response with initial salvage therapy and relapsed in the brain alone." The patient received cisplatin and etoposide as adjuvant treatment to surgical removal of the tumor. "Otherwise," Einhorn said, "we saw no example of third-line therapy, where we gave the same cisplatin plus [etoposide treatment], ever conferring any patient advantage or probability for survival." Ifosfamide is the first Treatment IND drug to come before an advisory committee for an approval recommendation since passage of the regulations. As such, the drug provides a potential test case for arguments by the research community that existence of a Treatment IND could delay the approval of the drugs. FDA's quick move in bringing the drug before the advisory committee just four months after submission of the NDA and approval of the Treatment IND supports the agency's stated position that Treatment IND drugs will not be reviewed with any less urgency than drugs without widespread availability. FDA has been under pressure from the oncologic research community to approve new cancer agents. At a joint National Cancer Institute/FDA meeting last fall, NCI researchers took the agency to task for delaying cancer drug approvals ("The Pink Sheet" Oct. 5, T&G-8). The committee recommended approval for Ifex despite a number of complicating factors. In addition to the fact that the NDA is based on a single-center study with a historical control, third-line treatment of testicular cancer is an orphan indication with an estimated annual patient population of only 200. In addition, an NDA for mesna has not yet been submitted and oncologists would still have to go through the Treatment IND process to follow recommended label directions for ifosfamide. At the meeting, FDA reiterated its philosophy that Treatment IND drugs should be evaluated based on available safety and efficacy data, and not on the existence of Treatment IND status. FDA Office of Drug Evaluation and Research I Director Robert Temple, MD, told the committee that it is FDA's "policy" that "availability of a Treatment IND is not a determining event" in evaluating the approvability of an NDA. However, FDA reviewing officer Gerald Sokol, MD, told the committee that it should not prematurely approve the drug for compassionate reasons since the drug is available. "There is a Treatment IND available so that . . . there is not immense humanitarian compulsion necessarily to approve this if more data is felt to be needed by the committee," Sokol said. Acting Committee Chairman Robert Capizzi, MD, Bowman Gray School of Medicine, Winston-Salem, North Carolina, also instructed the committee not to evaluate the NDA based on the availability of ifosfamide under a Treatment IND. "For the record, this committee will not review [the data] . . . based on availability of the therapy," Capizzi said. One of the committee's concerns in recommending approval was that once approved, ifosfamide would be used for other indications and treating physicians would have to be able to obtain mesna. Temple told the committee that he "would expect that labeling would have a fairly strong statement that says you shouldn't be using this unless you can get mesna." Temple also noted that "there is some possibility that mesna will be available relatively close to the time" that ifosfamide is available.

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