Forest Laboratories Inc.may face a head-to-head trial as a post-marketing commitment for aclidinium bromide after several advisory committee members told FDA the product should be compared to tiotropium at the same time lingering safety questions are explored.

Members of the Pulmonary-Allergy Drugs Advisory Committee also said more practical data should be generated post-market to help physicians and patients make treatment decisions. Forest is seeking approval of aclidinium bromide for treating bronchospasm from chronic obstructive pulmonary disease.

Committee chair Jerry Krishnan, University of Illinois, called for a “pragmatic trial” – saying practitioners need to know if aclidinium would add any value in the treatment armamentarium. He also suggested the agency include some patient-centered outcomes in the trial to show more effects on patients, such as improvement in a six-minute walk test.

“Having an alternative that is in current practice will provide a more complete picture of where does this new drug fit with what else we have on the shelf,” Krishnan said during the Feb. 23 advisory committee meeting.

“It would be enormously helpful to decision-makers that are not necessarily all represented at this table. And that will allow, I think, a more thoughtful discussion about the relative efficacy or if it’s pragmatically designed, relative effectiveness.”

Advisory Committee Votes

Do the efficacy data provide substantial evidence of a clinically meaningful benefit? 14-0 in favor
Has the product’s safety been adequately assessed for the proposed indication? 10-3 in favor, with one abstention
Do the efficacy and safety data provide substantial evidence to support approval? 12-2 in favor

Krishnan said the clinical trial population should better reflect the patients who would be expected to use aclidinium bromide.

“In part we need to have a better idea of how treatment occurs in practice and to the extent to which the design of the study could be plugged into practice,” he said. “You then allow a more applicable data set to whatever evidence you generate.”

The committee gave a positive recommendation for aclidinium bromide, deciding overwhelmingly that the data supported efficacy and safety. It also gave a resoundingly positive vote to recommend approval, although several members admitted their votes were reluctant.

FDA had concerns about cardiovascular events that occurred during the clinical trials. Reviewers said the significance of the findings was uncertain, but could not easily dismiss them. The agency also said the safety database that had been generated for the product met international guidelines, but was small compared to other COPD programs.

Committee members shared the concern and several said additional post-marketing trials should include studies of cardiovascular safety ([A#14120223005]).

Forest Willing To Discuss Post-Marketing Options

After the final votes, where committee members called for a post-marketing study, FDA asked for additional comments from committee members on the post-marketing trial proposal Forest had submitted, but that had not yet been reviewed by the agency.

FDA officials said they had substantial leeway for post-marketing trial designs and committee members’ advice could be useful.

The company said it planned a randomized trial with about 4,000 patients followed for three years. It would compare placebo plus the standard of care to aclidinium bromide and study the effect on severe exacerbations as well as look at cardiovascular safety.

Panelists voiced preference for requiring a head-to-head comparison in the trial because it would gather more information about it and Boehringer Ingelheim GMBH’s Spiriva (tiotropium), the only other member of the class aclidinium is seeking to enter.

Consumer representative Sidney Wolfe, director of Public Citizen’s Health Research Group, said one of the goals of the study should be to enhance the safety database. That would include reducing the number of potential participants who were excluded because of cardiovascular risk factors.

Some committee members questioned the criteria, which included excluding patients who had a myocardial infarction within the previous six months or who had been hospitalized with a class three or four heart failure within the previous six months, from participating in Forest’s studies.

Forest said the criteria were designed to not enroll patients who were unstable, and FDA said the study population and exclusion criteria were typical of other COPD-related development programs.

Wolfe argued for a study comparing aclidinium to tiotropium, as well as a placebo arm, but indicated it may be difficult to negotiate as part of a post-marketing commitment.

“Much more information would come from that, not only about this drug but also about tiotropium,” he said. “Understandably companies do tend to stay away as much as they can from doing head-to-head studies and I think this is a good time to do it.”

Marco Taglietti, Forest Research Institute president and chief medical officer, said after the committee meeting the company was willing to discuss potential post-marketing trial designs with FDA, including particular study aspects that would satisfy the needs of the COPD community.

“Right now there are not many cases where the agency has asked for a head-to-head comparison,” he said. “It’s difficult to speculate about what they would like to see.”

A registry that would include tracking cardiovascular outcomes and cardiopulmonary side effects also would be useful in answering safety questions, said committee member William Calhoun, University of Texas Medical Branch.

Head-to-Head Trial Could Create Commercial Concerns

A head-to-head comparison may not create an ideal situation for aclidinium if it enters the marketplace, as it could set it up for a commercial disappointment. Forest expects to push use of aclidinium as an alternative to tiotropium.

Throughout the advisory committee meeting, company officials arguing in favor of the product indicated COPD clinicians and patients need more treatment options. Forest is not claiming aclidinium is superior to other products.

Forest’s Taglietti said after the meeting he believes aclidinium will be differentiated from tiotropium in part through its twice-daily administration and device.

Those differences may be overlooked, however, if a post-marketing trial revealed the product did not perform as well as tiotropium or did not have a comparable safety profile.

Speaking for the sponsor, aclidinium investigator Stephen Rennard, University of Nebraska Medical Center, said physicians want to individualize COPD therapy and need multiple treatments to do so.

“Tiotropium is a really good drug, but the COPD population will benefit by having another anticholinergic,” Rennard said after the meeting.

Advisory committee member Timothy Lesar, Albany Medical Center, seemed unsure about couching the drug as an alternative.

“My one concern is that this will be perceived as a tiotropium me-too … and will be used as such,” he said. “It’s clearly not a first-line drug.”

Forest proposed the trade name Tudorza Pressair for aclidinium bromide, a product it is hoping will increase the company’s position in the COPD market; Forest currently markets Daliresp (roflumilast), another product used in COPD treatment. Forest is in need of new entries to offset revenue lost due to the expiration of patents for the antidepressant Lexapro and Alzheimer’s drug Namenda Also see "Positive COPD Data Allows Forest To File For Approval of Eklira in 2011" - Pink Sheet, 5 January, 2011..

An approval decision is expected from FDA about April 30 or earlier.

Panel Pushes For “Pragmatic” Post-Marketing Study, Head-To-Head Comparison For Forest’s Aclidinium

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