WASHINGTON - At its Oncologic Drugs Advisory Committee hearing for Evacet as a first-line treatment of metastatic breast cancer, the Liposome Co. Inc. last week was set upon by FDA officials who attacked key aspects of its clinical trials and ODAC members who rejected the basic premises of the clinical development program the company and FDA agreed on five years ago.

Evacet is a liposomal version of doxorubicin, a widely prescribed chemotherapy that can cause serious or fatal heart damage. Providing doxorubicin a liposome coating was intended to limit uptake of the drug by cardiac tissues. LIPO's strategy was premised on the assumption that because doxorubicin is widely prescribed, the main hurdle to winning marketing approval would be demonstrating a superior safety profile.

FDA encouraged this approach, allowing the company to base its clinical trials on a surrogate measure of efficacy - tumor response - rather than the survival benefit that other first-line metastatic breast cancer therapies have been required to demonstrate.

The strategy backfired when FDA and ODAC posed tough questions about negative survival data, which LIPO's trials left it unable to answer. According to LIPO, this focus was inappropriate and, given the agency's commitment to allow approval based on tumor response, unfair.

The agency and ODAC, however, argued that it is impossible to overlook survival data, and that, plus flaws in the trials, were sufficient to sink the application.

In the end, the committee voted 9-2 against Evacet (see BioCentury Extra, Sept. 17).

Data unravels

LIPO initially tried to obtain approval for Evacet based on two Phase III trials. In the pivotal trial, which compared Evacet plus cyclophosphamide to the same doses of doxorubicin plus cyclophosphamide, the primary end points were time to cardiotoxicity