Forest Laboratories Inc. got hesitant, but positive, support Thursday for approval of its inhaled aclidinium bromide as a twice-daily treatment for bronchospasms associated with chronic obstructive pulmonary disease (COPD).

The FDA's Pulmonary-Allergy Drugs Advisory Committee (PADAC) voted 12-2 to recommend approval for the long-acting antimuscarinic agent. But many of the members voting yes said they did so reluctantly due to unanswered safety questions, and they all agreed a large, robust postmarketing trial is needed to analyze cardiovascular risks.

The committee voted unanimously that aclidinium demonstrated efficacy as a bronchodilator, but it voted 10-3, with one abstention, on the drug's safety profile. Judith Currier, the patient representative on the committee, said she abstained because she thought the trial sample was too low to adequately assess cardiovascular risks, yet the sample size met regulatory guidelines.

New York-based Forest developed aclidinium, a new molecular entity in the antimuscarinic class, with Almirall SA, of Barcelona, Spain, to provide another treatment option for COPD patients.

Its aim was to demonstrate efficacy similar to that of other approved treatments, such as once-daily Spiriva HandiHaler (tiotropium bromide/Boehringer Ingelheim), Henry Sacks, executive director of respiratory clinical development at Forest, told the committee.

Since aclidinium, which Forest hopes to market as Tudorza Pressair, offers no unique benefit to balance out potential risks, panel member Sidney Wolfe, director of the Health Research Group of Public Citizen, voted against approval until a safety study is conducted.

However, if the FDA approves the drug, it should require a postmarketing study as soon as possible to look at cardiovascular risks, he said.

The other no vote came from Judith Voynow, professor of pediatrics at Duke University Medical Center. She also cited the inability to assess safety concerns from the limited data from Forest's Phase III program.

While FDA reviewers didn't assert a definitive drug-related cardiovascular concern with aclidinium, they noted the inability to eliminate that risk because of limited long-term safety data for the drug. (See BioWorld Today, Feb. 22, 2012.)

The size of Forest's studies was designed in accordance with FDA-adopted guidelines from the International Conference on Harmonisation (ICH), Sacks said. Those guidelines call for a drug to be tested in 1 ,500 subjects. Forest tested the 400 microliter dose of aclidinium in 1 ,471 patients.

While the FDA acknowledged that Forest met the ICH guidelines, it said the company needed to go further, especially in light of the large safety studies conducted for drugs already approved in the class.

For instance, the four-year, 6,000-patient Spiriva UPLIFT trial had double the safety database that aclidinium had, FDA reviewer Jennifer Rodriguez Pippin said. And Spiriva Respimat currently is in a large safety trial to get U.S. approval.

Ironically, some of the committee members said the UPLIFT results, which came back clean, made them feel more comfortable about the safety of aclidinium.

Much of the discussion Thursday focused on what the FDA requires in safety studies and what Forest's Phase IV study should look like.

When asked what is expected for a clinical trial to be adequately powered for safety, an FDA reviewer said typically the agency doesn't expect them to be powered for safety. Instead, the staff works with the sponsor as possible safety signals emerge.

As for the size needed for a safety trial, the reviewer said the agency hasn't indicated what it would expect.

The same ambivalence came up in defining "clinically meaningful." The reviewer said it is easier to say what isn't clinically meaningful than to say what is.

Noting that it has yet to discuss the trial design with the FDA, Forest unveiled a proposed three-year, 4,000-patient, randomized, placebo-controlled, postmarketing trial that would look at aclidinium's efficacy in COPD exacerbations, as well as cardiovascular safety.

Echoing comments from other committee members, Chairman Jerry Krishnan, a professor and associate vice president for population health sciences at the University of Illinois Hospital and Health Sciences System, said patient-centered outcomes should be part of the postmarketing study.

Krishnan and Currier both urged the FDA to make such endpoints standard in COPD trials as they are the endpoints that matter to patients.

Krishnan also said Forest's postmarketing trial should have an active comparator.

If aclidinium provides an added value in some way over current drugs, clinicians need to know that. When there are other approved treatments for a disease or condition, sponsors should end their obsession with placebo controls, he added.

Richard Honsinger, a clinical professor at the University of New Mexico School of Medicine, agreed.

He said he would have an ethical problem with putting patients in a postmarketing placebo-controlled trial when there are approved treatments available.

Noting the small percentage of African Americans included in the Phase III trials, the committee also encouraged Forest to get a broader population involved in the postmarketing trial.

"The time has come to think through how that might affect our postmarket studies," Krishnan said.

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