FDA Panel Reviews Pneumonia Indications for Doripenem

ROCKVILLE, MD. — A Food and Drug Administration advisory panel was split on whether the efficacy and safety data on doripenem, an injectable, broad-spectrum antibiotic, were adequate to support its approval for treating nosocomial pneumonia including ventilator-associated pneumonia.

At a meeting of the FDA's Anti-Infective Drugs Advisory Committee, the panel voted 7 to 6 that the clinical efficacy data from two noninferiority studies comparing doripenem with other antibiotics supported approval of the drug for this indication. The panel voted 8 to 5 that doripenem was safe for treating patients with nosocomial pneumonia including ventilator-assisted pneumonia (VAP) based on the trial data.

Johnson & Johnson Pharmaceutical Research and Development has proposed that doripenem be approved for treating nosocomial pneumonia, including VAP.

Those voting against approval had concerns about the studies, which included irregularities in the data and excess mortality in patients in one of the two studies among doripenem-treated patients. Several of those voting yes said they were supporting approval with reservations, citing the same reasons.

Doripenem, marketed as Doribax, was approved in October 2007 for treating complicated urinary tract infections and complicated intra-abdominal infections. Doripenem is a carbapenem in the β-lactam class of antibacterial agents that has broad antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria, according to the company.

The data submitted for approval included two phase III, multicenter, randomized, open label, active control studies of adults with clinical, radiologic, and microbiologic evidence of nosocomial pneumonia, conducted by Johnson & Johnson. One study compared doripenem with piperacillin/tazobactam in nonventilated patients with nosocomial pneumonia and those with early-onset VAP (occurring within the first 4 days of hospitalization). The second study compared doripenem to imipenem, another carbapenem antibiotic, in patients with early-onset VAP and late-onset VAP (occurring after 5 or more days of hospitalization).

Both studies were designed to establish “noninferiority” between doripenem and the other treatments, based on the clinical cure rate 6–20 days after treatment was completed. The clinical cure rate was defined as “complete resolution or marked improvement or return to baseline of all signs and symptoms of pneumonia and improvement or lack of progression of all chest x-ray abnormalities, such that no additional antibacterial therapy was required.”

In the study of patients with non-VAP and early-onset VAP, the clinical cure rates were 81.3% among those who received doripenem and 79.8% among those who received piperacillin/tazobactam. In the study of patients with early and late-onset VAP, the clinical cure rate was 68.3% among those treated with doripenem, compared with 64.8% of those who received imipenem. Adverse events were similar to those seen with doripenem for other approved indications, and with carbapenems, and “in general, was similar” to the adverse events in patients on the comparator antibiotics, according to the company.