BETHESDA, Md--The FDA's Oncology Drugs Advisory Committee (ODAC) voted 8 to 4 to recommend that the agency grant traditional new drug approval to Bristol-Myers Squibb's Taxol for Injection Concentrate (paclitaxel) for the second-line treatment of AIDS-related Kaposi's sarcoma (KS).
The four naysayers to the vote, however, made clear that they did not oppose approval, but wanted it to come under the FDA's accelerated approval process. Their comments indicated they felt a need for further study of Taxol's benefit in treating AIDS-related KS, the most common AIDS-related malignancy.
Under the traditional new drug approval system, in effect since 1962, drug companies must prove their drugs safe and effective, based on adequate and well-controlled clinical trials. "Efficacy must represent clear patient benefit," the FDA specifies. An improvement in response rate is not considered adequate to demonstrate efficacy .
Under the newer accelerated approval regulations, however, drugs for serious or life-threatening illnesses can be approved on the basis of an improved patient response over available therapy. However, such approval is "subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit," according to the FDA.
"With the committee's favorable reception of the data, we hope for a rapid FDA approval," said Rick Winningham, president of Bristol-Myers Squibb's Oncology/Immunology Division, in a statement released immediately after the vote. "This is another major step for the company in its ongoing commitment to explore new uses for Taxol."
The FDA approved Taxol in December 1992 for second-line use in treating metastatic breast and ovarian cancers. The drug, derived from the Pacific yew tree, is a novel agent that stabilizes cell microtubules. This, in turn, inhibits the normal reorganization of the microtubule network, an essential element in cell division and other vital cell functions.
Two Phase II Trials
To support its request that Taxol be approved for use against Kaposi's sarcoma, the company presented combined data from two phase II trials.
Trial 139-281 was carried out at the University of Southern California (USC) and the Massachusetts General Hospital, with patients receiving 100 mg/m² of intravenous Taxol over 3 hours every 14 days. In trial 139-174, conducted at the National Cancer Institute, patients received 135 mg/m² of the drug intravenously over 3 hours every 21 days.
A total of 85 patients participated in the studies, but the company's analysis focused on the 59 patients who had received prior systemic chemotherapy. Bristol-Myers Squibb's contended that 37 of the 59 patients (63%) showed a cutaneous tumor response rate, with a median duration of 9.1 months. FDA reviewers discounted two patients as responders and put the response rate at 59%.
The company's analysis also showed that 11 of 12 patients in the combined studies who had foot KS improved, as did 34 of 41 with edema and 12 of 19 with facial KS. Performance status improved in 13 of 21 patients, and KS-related pain improved in 4 of 21 patients.
The FDA reviewers found "evidence of significant clinical benefit from treatment with Taxol," though they were not in universal agreement with the company as to the extent of benefit. For example, the FDA found evidence of improvement in only 6 of the 12 foot KS patients and in 10 of 19 patients with facial KS.
Neutropenia was common among the KS patients--100% in trial 139-174, said Robert Yarchoan, MD, of the NCI--as was anemia (73%). A few patients, 9% in the NCI study, suffered febrile neu-tropenia. A similar pattern of side effects, but with fewer percentages of patients, was observed in the USC/Mass General study, which used the lower dose of the drug. "Therapy was well tolerated with a median duration of 10 Taxol courses," said Parkash S. Gill, MD, of USC.
Even with a greater incidence of toxicity, the company sought to have the drug approved at the higher dosage. Benjamin Winograd, MD, director of oncology clinical research, said that Bristol-Myers Squibb felt "more comfortable" with the outcomes at that level.
The ODAC Vote
The FDA staff asked ODAC to address four questions after hearing the presentations. The advisory panel agreed 11 to 0 that the evidence supported the efficacy of Taxol in patients with AIDS-related KS. It also agreed by an 8 to 3 vote that the sample size from the two phase II studies was adequate to show efficacy.
The panel declined to make a recommendation on whether the treatment dose be set at 135 mg/m² every three weeks, as proposed by Bristol/Myers Squibb. ODAC member David H. Johnson, MD, of Vanderbilt University, suggested it would be better if the FDA simply "put both sets of data into the package insert and let the clinician make the decision."
The panel split in its decision to recommend that the FDA grant traditional new drug approval to Taxol for the new indication, with the four dissenters noting their preference for recommending approval under the FDA's accelerated approval process