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Executive Summary

Bristol-Myers Squibb's NDA for a first-line therapy indication for Paraplatin (carboplatin) in stage III and IV ovarian cancer is viewed favorably by FDA, according to a presentation at the July 1 meeting of FDA's Oncologic Drugs Advisory Committee. FDA reviewer Grant Williams, MD, stated that clinical trial data submitted in the company's supplemental NDA support the safety and efficacy of Paraplatin as a first-line treatment in comparison to the standard therapy, Bristol's Platinol (cisplatin). The committee was not asked to make an approval recommendation. Paraplatin, an analog of the older drug Platinol, is currently approved as a single agent for the palliative treatment of recurrent ovarian cancer after prior chemotherapy, including patients previously treated with cisplatin. The first-line use application is based on the results of two trials comparing Paraplatin and Platinol in combination with cyclophosphamide in a total of 800 ovarian cancer patients. The trials were conducted by the Southwest Oncology Group (SWOG) in the U.S. and by the National Cancer Institute of Canada (NCIC). "Bristol has shown that for the two populations of patients with advanced ovarian cancer represented by the SWOG and NCIC trials, overall survival and overall time to progression [of disease] are equivalent when carboplatin is substituted for cisplatin and when both are given in combination with cyclophosphamide," Williams said in his review of the data. As in earlier trials, patients receiving carboplatin also exhibited fewer non-hematologic toxic side effects, such as nausea and vomiting. Paraplatin was approved with a "1B" rating (moderate therapeutic advance over existing therapies) in March of 1989, only nine months after Bristol-Myers submitted the NDA ("The Pink Sheet," March 13, 1989, T&G-1). The product was recommended for approval by the Oncologic Drugs Advisory Committee at its Dec. 19, 1988 meeting. At that time, the committee suggested that carboplatin's indication be limited to second-line treatment of relapsed patients, concluding that additional data would be needed to approve Paraplatin as first-line therapy. At the July 1 meeting, Office of Drug Evaluation I Director Robert Temple, MD, noted that the primary hold-up in approving Paraplatin as a first-line therapy was that comparative survival data on Paraplatin versus Platinol were not "mature" at the time of the original NDA approval. He recalled the ongoing debates between FDA and the National Cancer Institute on identifying endpoints for cancer drug trials and approvals and reiterated FDA's past position that defining endpoints in a particular disease is "a function of whether the therapies that are available at the time have an impact on survival or not, and if so how great an impact." Temple explained that "in ovarian cancer . . . it was concluded that cisplatin does have an impact on survival . . . Therefore, the committee felt that it was appropriate that the data be mature enough to conclude that the use of carboplatin would not be associated with worse survival." At the time of the 1989 approval, NCI cited the Paraplatin review as an example of what it saw as FDA's overcautious new cancer drug approval process. NCI maintained that limited efficacy data is all that FDA should have needed as a basis for Paraplatin's approval because of the agent's superior safety profile compared to Platinol ("The Pink Sheet," Feb. 6, 1989, p. 5). Like cisplatin, carboplatin is licensed from the National Institutes of Health, where research on the compounds was pioneered. FDA's Williams indicated that the survival profile of carboplatin is still a concern at the agency. He pointed out that because the late-stage ovarian cancer patients enrolled in the SWOG and NCIC trials entered the trials with poor prognoses, analysis of carboplatin's efficacy in patients with stronger prognoses was not possible. Since it is unknown whether carboplatin or cisplatin is more likely to be effective in producing the relatively rare cases of long-term survival and cures in ovarian cancer patients, Williams said, it is important "that oncologists realize the limitations of the proof of equivalence, and realize where educated guessing begins." BMS has agreed to place statements in advertising and labeling alerting physicians of the uncertainty of the long-term survival data and "qualifying the claim of proof of equivalence in overall survival," Williams said. Paraplatin as now approved for second- line therapy also carries a survival data statement. The agreed-upon first-line therapy statement will read: "In two trials, Paraplatin demonstrated an equivalent overall survival rate compared to cisplatin when both were given in combination with cyclophosphamide. Study design limits statistical power for equivalence in patients with less than 2 cm residual tumor and for pathologic complete response rate and survival greater than three years." Discussing FDA's presentation, several committee members raised the question of whether the deficiencies in long-term survival data for Paraplatin were any greater than those for other products. Committee Chairman Craig Henderson, MD, Harvard Medical School, said: "Most of the committee seems to be comfortable with the statement that [Paraplatin and Platinol] are equivalent in terms of efficacy . . . Several of the committee question whether they [FDA] really need to emphasize the limitations" of the data on survival. Paraplatin's current narrow indication has helped put the product in the midst of a number of regulatory debates in recent months, including those on off-label drug use, insurer reimbursement for experimental drug use and promotion of unapproved uses. In February, the General Accounting Office's report on off- label use of cancer drugs found that 105 oncologists out of a surveyed 1,400 reported using Paraplatin off-label for 17 different unapproved uses; the doctors cited the compound as a frequent source of reimbursement disputes with insurers who denied payment for the off-label uses ("The Pink Sheet," March 4, p. 18). Paraplatin surfaced again in the dispute between Bristol-Myers Squibb and FDA over cancer drug promotion/education materials. FDA found in February that Bristol-sponsored "Oncology Commentary '90" medical literature, which included discussion of Paraplatin as a therapy for non-small cell lung, bladder, head and neck cancers, crossed the line between education and illegal promotion of off- label uses ("The Pink Sheet," Feb. 11, p. 12). Bristol recently settled the promotion issue with the agency on the "Oncology Commentary" material by sending out "Dear Doctor" letters alerting oncologists that, in the agency's judgment, the material is promotional and not scientific ("The Pink Sheet" June 3, p. 4).

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