Persistent cardiovascular events across the clinical trials for aclidinium bromide may not represent a definite safety signal, according to the Food and Drug Administration, but there is enough concern that an advisory committee will be asked for input on its significance.

The drug’s maker, Forest Laboratories Inc., wants approval of aclidinium bromide for long-term maintenance treatment of bronchospasm from chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. It comes as a dry powder and is dispersed through an inhaler from Almirall SA.

When the FDA’s Pulmonary-Allergy Drugs Advisory Committee considers the product on Feb. 23, the agency wants the panel to discuss the overall safety profile, given the size of the safety database and duration of exposure. The committee also will vote on whether safety has been adequately assessed for the proposed indication.

FDA reviewers identified 10 cardiovascular deaths among patients in aclidinium clinical trials who were treated with the desired 400-mcg dose.

Four of those deaths were caused by cardiac arrest and one was from acute cardiac failure, while only one case of myocardial infarction was reported in patients receiving a 200-mcg dose of aclidinium bromide. None was reported among those receiving placebo. A cardiovascular cause could not be ruled out in two placebo cases, according to FDA documents.

The clinical reviewer said that the significance of the findings is uncertain, but called it "striking" that all the CV deaths in the long-term safety trial were in the 400 mcg–dose group.

Still, the agency said that the incidence rate in the group is lower than would generally be expected in a "real world" COPD population.

"It is difficult to dismiss the apparent imbalance in cardiovascular death between the treatment groups, while at the same time, impossible to conclude that the data represent a true safety signal," the clinical briefing documents conclude.

The size of the safety database was concerning to the FDA. Across all Forest’s trials, 1,471 patients with COPD were exposed to the 400-mcg dose with a mean duration of 211 days, including 733 patients exposed for 182 days or more and 329 exposed for 1 year.

The agency said the size was consistent with international guidelines but was "relatively small compared to the size of programs for other COPD products."

Long-term data combined with additional exposure data suggest that the CV death was possibly dose dependent, the agency said.

"Whether these results represent a spurious finding or a potential safety signal is difficult to discern and may warrant further investigation," the FDA stated.

FDA said the issue is particularly important given the possibility of increased mortality that has been identified with other inhaled anticholinergic agents.

Last year, the FDA ordered large studies of four long-acting beta agonists (LABAs) to assess their safety when used with inhaled corticosteroids versus inhaled corticosteroids alone. It was an outgrowth of a reanalysis of trial data that found LABA use can be associated with severe asthma symptoms, hospitalization, and death.

The FDA said that the reanalysis could be interpreted in different ways and decided new studies were needed.

If the committee decides aclidinium bromide’s safety has not been assessed adequately, it will be asked what other data should be obtained.

Efficacy Data Not Questioned

FDA reviewers did not have any doubts about whether aclidinium bromide’s efficacy had been demonstrated in the three trials that were submitted. The agency said a statistically significant effect compared with placebo was found for the 400-mcg dose, as well as a smaller significant effect for a 200-mcg dose, after 12 weeks of treatment.

02/22/12