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12:00 AM
 | 
Jun 08, 2009
 |  BioCentury  |  Regulation

The Old Rules are Capped

Last week's meeting of FDA's Anti-Infective Drugs Advisory Committee put a punto final to the old way of developing drugs for the less serious forms of community-acquired pneumonia that are treated on an outpatient basis, as both FDA and the committee made clear they would apply the agency's new guidelines to compounds in development before the regime was put in place.

While that could potentially mean the end of the road for Advanced Life Sciences Holdings Inc.'s Restanza cethromycin, which was the last compound in development under the old system, the agency says it doesn't mean new drugs couldn't be developed under its new draft guidelines.

Prior to an April 2008 meeting of AIDAC, FDA had previously determined that compounds for self-resolving infections would require either placebo-controlled or superiority trial designs, while trials of compounds for serious infections requiring hospitalization or infections in already-hospitalized patients would be able to use non-inferiority designs.

The 2008 committee meeting addressed the remaining gray area: how to test drugs for the less serious forms of CAP that are treated on an outpatient basis. The key decision was that, based on historical data, a trial showing non-inferiority (NI) with a margin of 10% would be appropriate (see BioCentury, April 7, 2008).

Advanced Life had been in discussions with the agency and told BioCentury in October 2008 it had met the new requirements when it submitted an NDA for Restanza, an oral ketolide antibiotic, to treat mild-to-moderate CAP (see BioCentury, Oct. 13, 2008).

The NDA was supported by two international Phase III studies with a primary endpoint of clinical cure that demonstrated non-inferiority to Biaxin clarithromycin with a 10% margin. Biaxin, a semi-synthetic macrolide antibiotic from Abbott Laboratories, is standard of care in CAP.

The trials, CL05 and CL06, were conducted in 2005-07 and enrolled patients the company deemed likely to be treated as outpatients.

FDA's analysis of the data and last week's AIDAC review of the NDA made it clear the company had not cleared the hurdle.

The agency sliced the trial into subpopulations according to disease severity criteria laid out in draft guidance issued this March. That guidance, which grew out of the 2008 AIDAC meeting, recommended that all clinical trials of oral antibiotics for CAP - even those for mild-to-moderate disease - be conducted in patients with more serious disease.

The reason for that recommendation was that historical efficacy rates - on which any non-inferiority trial would be based - are known only in patients with severe disease (see Online Links, A28).

In practical terms, this means that enrolled patients must have a minimum patient outcome research team (PORT) score of 2 and that at least 50% must have scores...

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