West Coast Editor

It's a phrase that can send shivers down the spine of almost any biotechnology leader - "refusal to file" - and Cardiome Pharma Corp. heard it late last month with regard to RSD1235, the company's drug for arrhythmia.

Vancouver, British Columbia-based Cardiome's partner, Astellas Pharma US Inc., in late March filed the new drug application, but was told by the FDA that "inconsistencies and omissions in the database" made the NDA unacceptable. Intravenous RSD1235 is for acute conversion of atrial fibrillation. (See BioWorld Today, June 1, 2006.)

Cardiome's shares (NASDAQ:CRME) plunged 20 percent on the news, to close at $9.03 on the FDA's action, which CEO Bob Rieder said was "more of an execution error" than anything else.

Rieder said the letter from the agency "does not in any way allude" to inadequacies in the data package. The FDA's published guidance on RTFs says the action generally is taken because of "omissions of clearly necessary information (not a matter of interpretation or judgment), such as information required under the statute or regulations or omissions or inadequacies so severe as to render the application incomplete on its face."

Brett Holley, analyst with CIBC World Markets in New York, wrote in a research note at the time that the issues relate to "inconsistencies in case reports between sections of the NDA," and cited a "very low likelihood" that more data would be needed. He predicted an approval delay of three to four months, or six months at worst.

Holley met with Cardiome's management Wednesday and learned the FDA letter "pointed out inconsistencies in the tabular summary of data for a patient, which led the agency to question the NDA's overall reliability," according to his follow-up report, which said Cardiome described regulators as "supportive of preliminary refiling plans."

He wrote that he expects the firm's stock to rebound. Meanwhile, Cardiome is asking Astellas to pay immediately the $10 million milestone that was due on acceptance of the NDA, and to assume all costs related to the refiling. Cardiome also wants Astellas to pay for a third party to audit the redone NDA before filing.

A much-publicized RTF involved Erbitux (cetuximab), the troubled but ultimately approved colorectal cancer drug from ImClone Systems Inc. and Bristol-Myers Squibb Co., both of New York. A rolling biologics application was filed in the fall of 2001, and in late December came the RTF. (See BioWorld Today, Sept. 20, 2001, and Jan. 1, 2003.)

But it's happened before. An example is Oscient Pharmaceuticals Corp.'s Factive (gemifloxacin mesylate), the FDA-approved tablet for acute bacterial exacerbations of chronic bronchitis and mild to moderate community-acquired pneumonia. Oscient, of Waltham, Mass., got an RTF regarding its supplemental NDA to gain approval of the drug for acute bacterial sinusitis.

The firm was able to have its sNDA filed "under protest," with a decision date slated for mid-December and an advisory panel expected to convene this fall.

Another recent case involves Cipher Pharmaceuticals Inc.'s formulation of the acne drug isotretinoin, which garnered an RTF letter last September. The Mississauga, Ontario-based firm kept working with the FDA, and in an approvable letter about a month ago, the agency asked for more clinical data.

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