Washington Editor

SILVER SPRING, Md. - The FDA's Oncology Drugs Advisory Committee on Thursday disagreed with a shortened approval pathway for Abraxane (paclitaxel) as an adjuvant breast cancer treatment, which would expand its label.

The drug already is marketed for metastatic breast cancer, and its maker, Abraxis BioScience Inc., applied for broader, earlier use under Section 505 (b)(2) of the Food, Drug and Cosmetic Act. That rule allows for approvals of new formulations of already marketed drugs by referring to studies supporting those original approvals instead of conducting new studies.

Instead, panel members voted 13-1 that the product should be tested in a controlled, randomized trial to more definitively evaluate its safety and efficacy in this setting. "To me, the burden is safety and assured efficacy," said Maha Hussain, the committee's chairperson and a professor of medicine at the University of Michigan. "I think a study should be done."

Company executives declined to comment after the verdict, but said later in a press release that it was "encouraged" by the recommendation and will "move as quickly as possible" to meet with the FDA and decide on the next steps.

The recommendation might "enable approval in this indication earlier than typically expected," said Michael Hawkins, chief medical officer at Abraxis.

Shares in Abraxis (NASDAQ:ABBI) lost 8 cents Thursday to close at $24.97.

According to the FDA's Richard Pazdur, such a trial would likely test the product's non-inferiority to its reference drug in the 505 (b)(2) application, Taxol (paclitaxel, from Bristol-Myers Squibb Co.), in a randomized, controlled evaluation in high-risk patients. He added that reviewers at the agency would "exercise regulatory discretion and flexibility" in designing a trial that doesn't tax the Los Angeles company in terms of excessive enrollment numbers.

Like all other FDA-approved adjuvant breast cancer treatments, Taxol was first approved in metastatic breast cancer and was subjected to a randomized, controlled study to prove its merit in the earlier setting, which Pazdur termed a "high-bar indication." While Abraxane's active ingredient is identical to Taxol, their formulations and pharmacokinetic profiles differ, so the two drugs are not bioequivalent, and that was central to the FDA's contention that a 505 (b)(2) approval is not appropriate for adjuvant breast cancer.

"The essential question," Pazdur said, "is one of risk-benefit to the American public."

Speakers for the company reported data showing that Abraxane is more effective than Taxol in metastatic breast cancer, a finding explained in part by its lack of a solvent called cremophor used in Taxol. Instead, Abraxane employs albumin, which allows for the safe delivery of higher doses of paclitaxel, 260 mg/m2, compared to 175 mg/m2 for Taxol. Therefore, they concluded it could be approved for adjuvant breast cancer without added study of its safety and effectiveness in that indication, proposing instead a safety comparison as a post-approval commitment.

"We believe that an efficacy trial in the adjuvant treatment of breast cancer is not scientifically necessary," Hawkins said, "and would significantly delay the approval of a cremophor-free paclitaxel alternative for physicians and their patients."

But Pazdur countered that Abraxane's "greater perceived efficacy" in metastatic breast cancer "doesn't obviate the need" for a randomized study in the adjuvant setting because such treatment is given with a curative intent. That was underscored by the FDA's Patricia Cortazar, who also stressed that Abraxane's benefit should be well established in a randomized, controlled trial powered for efficacy and safety.

The agency's concerns, she noted, center on the belief that adjuvant treatment gains made with Taxol "may not be maintained" with Abraxane. In particular, the FDA expressed unease with the products' different pharmacokinetic profiles and the higher levels of peripheral neuropathy seen in Abraxane-treated patients compared to those treated with Taxol in a metastatic breast cancer study.

Hawkins attributed the pharmacokinetic differences to the products' respective uses of albumin and cremophor, noting that Abraxane's pharmacokinetic profile is more predictable as a result. In addition, he pointed to a pilot adjuvant study of Abraxane in 30 patients showing that peripheral neuropathy symptoms subsided after eight months in 97 percent of them. Also, Abraxane's dosing schedule is more convenient than Taxol's delivery. Infusions with the former take far less time, 30 minutes compared to three hours, and don't require supplemental steroid treatment used prior to Taxol delivery to offset cremophor-related issues.

Still, such side-effect data and convenience factors weren't enough to convince the large majority of panel members that the products could be interchangeable as adjuvant breast cancer treatments in the absence of a study. The sole dissenting voice, Michael Perry of the University of Missouri, said "there's no sex" to such a study and added that "it would be hard" to recruit patients over an eight-year-or-more period to complete it.

Abraxane, which is partnered with London-based AstraZeneca plc, received FDA approval last year for metastatic breast cancer patients who have failed combination chemotherapy. In the quarter ended June 30, the product generated $36.3 million in revenue, an 87 percent increase, and the company's full-year forecast projects sales totals to range between $170 million and $190 million. Analysts have predicted the drug could bring in annual sales of $500 million over the next couple of years. (See BioWorld Today, Jan. 11, 2005, and April 28, 2006.)