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Executive Summary

LEDERLE NOVANTRONE LITERATURE-BASED SUPPLEMENTAL NDAS will be submitted to FDA by the end of the year for the use of the chemotherapy agent in treating relapsed leukemia and breast cancer patients. Novantrone (mitoxantrone) is currently indicated only as initial therapy for acute nonlymphocytic leukemia in adults, a category which includes myelogenous, promyelocytic, monocytic and erythroid acute leukemias. Lederle will not seek a sole-agent indication for Novantrone in breast cancer treatment; the firm said it is "willing to accept an indication that defines the niche" where the product may be most useful. This would include patients for whom side-effects are a particular concern. Approval of the supplemental NDAs would achieve three goals: allow Lederle to promote Novantrone for the two indications; provide clinicians with appropriate dosing information for breast cancer; and facilitate reimbursement from third-party payers. Novantrone would appear to be a logical candidate for FDA review for expanded indications based on literature reviews. The drug is widely used off-label and has a large library of published studies on its use. Novantrone's use in the U.S. for both relapsed leukemia and breast cancer is large: an estimated 55% of the drug's U.S. sales are for the breast cancer indication. A GAO survey of oncologists published in September 1991 reported that 85% of Novantrone use is off label ("The Pink Sheet" Sept. 30, 1991, T&G-5). "Several hundred" published studies of Novantrone use in breast cancer are available, including many large, well-controlled trials, Lederle said. The drug is approved in 15 foreign countries for the breast cancer indication. The company says the published literature shows Novantrone is associated with a smaller tumor response rate than doxorubicin (Adria's Adriamycin) in breast cancer patients, but that survival rates are about the same. In addition, Lederle says the literature shows that Novantrone is associated with a lower rate of cardiac side effects, alopecia, bone marrow suppression and mucocitis than doxorubicin. At a December 1987 meeting, FDA's Oncologic Drugs Advisory Committee voted against recommending approval of Novantrone for the treatment of breast cancer, reversing its decision of March 1986, when the committee voted seven-to-two that FDA should approve the drug for that indication. The reversal was based on the results of extensions to Lederle's efficacy trials that showed Novantrone had a 15% response rate, versus a 28% response rate for Adriamycin. Also, the median number of days to death was 188 for Novantrone and 315 for Adriamycin. Earlier data had not shown as wide a difference between the drugs. At the same December 1987 meeting, the advisory committee voted to approve Novantrone for the nonlymphocytic leukemia indication, but voted unanimously against the drug's use in relapsed or refractory nonlymphocytic leukemia. FDA Commissioner Kessler has been planning to send a letter to industry requesting companies to identify off-label uses of their products and information in the medical literature regarding those uses ("The Pink Sheet" June 15, p. 7). The agency has expressed a willingness to consider the possibility of approving supplemental NDAs based on literature reviews. The letter has not yet been sent, FDA said, because it is being reviewed in conjunction with the agency's second draft of its continuing medical education concept paper. Both documents are said to be under review at the upper levels of HHS. Lederle was not asked directly by FDA to submit any supplemental NDAs, but said it is proceeding with the submission because of "public comments made by FDA" to the effect that such supplements may be considered in the future. Once the supplemental NDAs are submitted, the company plans to meet with the agency to discuss the data. Another major chemotherapy marketer, Adria, says it has traditionally submitted supplemental NDAs based on clinical trials and that it is not working on any literature-based submissions. Issues surrounding off-label uses of cancer drugs for pediatric indications will be discussed at a Nov. 20 working group in Denver. The meeting is being organized by the Children's Cancer Group, a cooperative clinical trial group with 110 member institutions in the U.S. Insurance providers, pediatric oncology experts, and several marketers of oncologic drugs have been invited to discuss reimbursement issues and ways to speed regulatory approval for off-label pediatric cancer treatments. A tentative attendance list for the conference includes Bristol- Myers Squibb, Lederle, Adria and Malcolm Smith, MD, of the National Cancer Institute's cancer treatment division. FDA also has been invited to attend.

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