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12:00 AM
 | 
Mar 19, 2012
 |  BioCentury  |  Regulation

Feasible, perhaps not relevant

Urinary infections: Docs say FDA drug trials don't fit U.S. clinical practice

Two companies developing drugs to treat complicated urinary tract infections say it is feasible to conduct trials according to recommendations in FDA's new draft guidance. But clinicians are concerned the results of such studies won't be applicable to real-world clinical practice in the U.S.

A complicated urinary tract infection (cUTI) is characterized by pyuria and pathogen on culture of urine or blood, plus a functional or anatomical abnormality of the urinary tract, and is accompanied by symptoms such as fever, chills and back pain. For a minority of patients, cUTIs can be life threatening due to the risk of septic shock.

cUTI is viewed as an important indication for antibiotic development because it is generally the first indication companies pursue in the Gram-negative space. Gram-negative infections are widely agreed to be the biggest area of unmet need for antibiotics, as these pathogens are growing more and more resistant to existing antibiotic therapies and there are few antibiotics against them in development.

"That is why the emerging resistance is such a problem, because there are very few alternatives," said David Shlaes, president of Anti-Infectives Consulting LLC. Shlaes was previously VP of infectious diseases at Wyeth and EVP of R&D at Idenix Pharmaceuticals Inc.

The draft guidance on cUTI, released on Feb. 23, is similar to FDA's guidances on hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP), community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs).

All recommend superiority trials in cases of multi-drug resistance, but say non-inferiority studies are more likely to be conducted and should have a non-inferiority margin of 10%.

All the documents also propose excluding patients who have been treated with prior antibiotics, although the time frames for this exclusion differ (see BioCentury, April 7, 2008; Sept. 13, 2010; & Nov. 14, 2011).

The cUTI guidance recommends a combined primary endpoint of microbiological success and resolution of clinical symptoms. Microbiological success is defined as demonstrating that the bacterial pathogen found at trial entry is reduced to less than 10,000 colony-forming units/mL on urine culture.

Clinicians contacted by BioCentury say FDA's recommendations - especially exclusion of patients treated with antibiotics within 48 hours prior to enrollment, and a five-day dosing period for IV drugs followed by five to nine days of oral therapy - are not consistent with the way patients are or should be treated.

So far, so good?

Cubist...

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