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).
BETHESDA, Md--The FDA's Oncology Drugs Advisory Committee (ODAC) voted8 to 4 to recommend that the agency grant traditional new drug approvalto 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 notoppose approval, but wanted it to come under the FDA's accelerated approvalprocess. Their comments indicated they felt a need for further study ofTaxol's benefit in treating AIDS-related KS, the most common AIDS-relatedmalignancy.
Under the traditional new drug approval system, in effect since 1962,drug companies must prove their drugs safe and effective, based on adequateand well-controlled clinical trials. "Efficacy must represent clearpatient benefit," the FDA specifies. An improvement in response rateis not considered adequate to demonstrate efficacy .
Under the newer accelerated approval regulations, however, drugs forserious or life-threatening illnesses can be approved on the basis of animproved patient response over available therapy. However, such approvalis "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 hopefor a rapid FDA approval," said Rick Winningham, president of Bristol-MyersSquibb's Oncology/Immunology Division, in a statement released immediatelyafter the vote. "This is another major step for the company in itsongoing commitment to explore new uses for Taxol."
The FDA approved Taxol in December 1992 for second-line use in treatingmetastatic breast and ovarian cancers. The drug, derived from the Pacificyew tree, is a novel agent that stabilizes cell microtubules. This, inturn, inhibits the normal reorganization of the microtubule network, anessential 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'ssarcoma, 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 100mg/m² of intravenous Taxol over 3 hours every 14 days. In trial 139-174,conducted at the National Cancer Institute, patients received 135 mg/m²of the drug intravenously over 3 hours every 21 days.
A total of 85 patients participated in the studies, but the company'sanalysis focused on the 59 patients who had received prior systemic chemotherapy.Bristol-Myers Squibb's contended that 37 of the 59 patients (63%) showeda cutaneous tumor response rate, with a median duration of 9.1 months.FDA reviewers discounted two patients as responders and put the responserate at 59%.
The company's analysis also showed that 11 of 12 patients in the combinedstudies who had foot KS improved, as did 34 of 41 with edema and 12 of19 with facial KS. Performance status improved in 13 of 21 patients, andKS-related pain improved in 4 of 21 patients.
The FDA reviewers found "evidence of significant clinical benefitfrom treatment with Taxol," though they were not in universal agreementwith the company as to the extent of benefit. For example, the FDA foundevidence of improvement in only 6 of the 12 foot KS patients and in 10of 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 ofside effects, but with fewer percentages of patients, was observed in theUSC/Mass General study, which used the lower dose of the drug. "Therapywas well tolerated with a median duration of 10 Taxol courses," saidParkash S. Gill, MD, of USC.
Even with a greater incidence of toxicity, the company sought to havethe drug approved at the higher dosage. Benjamin Winograd, MD, directorof oncology clinical research, said that Bristol-Myers Squibb felt "morecomfortable" with the outcomes at that level.
The ODAC Vote
The FDA staff asked ODAC to address four questions after hearing thepresentations. The advisory panel agreed 11 to 0 that the evidence supportedthe efficacy of Taxol in patients with AIDS-related KS. It also agreedby an 8 to 3 vote that the sample size from the two phase II studies wasadequate to show efficacy.
The panel declined to make a recommendation on whether the treatmentdose be set at 135 mg/m² every three weeks, as proposed by Bristol/MyersSquibb. ODAC member David H. Johnson, MD, of Vanderbilt University, suggestedit would be better if the FDA simply "put both sets of data into thepackage insert and let the clinician make the decision."
The panel split in its decision to recommend that the FDA grant traditionalnew drug approval to Taxol for the new indication, with the four dissentersnoting their preference for recommending approval under the FDA's acceleratedapproval process