Medical Device Daily Washington Editor

GAITHERSBURG, Maryland — The idea of inserting ablative devices into the heart is old hat by now, but inserting an ablation device into the lungs is a novelty. Novel or not, the anesthesiology and respiratory devices advisory committee met Wednesday to review a PMA for just such a technology.

The sponsor of the Alair bronchothermoplasty system, Asthmatx (Sunnyvale, California) conducted the pivotal trial in a number of locations in the U.S., Australia and Brazil, but the data from Brazil diluted otherwise convincing safety and efficacy data, nearly torpedoing the application. However, the firm earned the panel's nod despite the confounding data thanks to a sharp reduction in visits to hospitals and emergency rooms among the patients in the study arm as compared to those in the control arm.

The Alair device is designed to ablate the main bronchial airways with radio frequency energy so as to reduce the thickness of smooth muscle mass and hence leave the patients with less susceptibility to asthma attacks. The proposed indication for the device is for patients over the age of 18 who are persistently and severely asthmatic, although there are signs that the Center for Devices and Radiological Health now see anyone under the age of 21 as a pediatric patient.

Gerald Cox, MB, of McMaster University (Hamilton, Ontario) reminded the panel that asthma afflicts roughly 22 million Americans and that while treatments for mild cases are usually fairly efficacious, more severe cases are not particularly well handled by the current inventory of anti-inflammatory medications. Long-term use of synthetic corticosteroids carries the risk of osteoporosis and other symptoms of Cushing's syndrome, including elevated serum glucose and obesity.

Cox also noted that while mild cases generate annual healthcare costs of about $2,200 a year, the annual cost of helping a patient with a severe case averages in excess of $12,000.

The firm had conducted a total of three trials including the pivotal trial, the AIR (Asthma Intervention Research) 2 trial, which was reviewed by Mario Castro, MD, of the Washington University School of Medicine (St. Louis). Castro said the trial had randomized 297 patients but that nine dropped out before any treatment had commenced. Of the remaining 288 patients, 20 did not stay with the follow-up of 12 months, leaving the sponsor with 268 patients per protocol.

The patients in the control arm of AIR 2 did well on the treatment – 76% of them returned the indicated numbers on a quality of life (QoL) questionnaire – but the patients in the sham arm of the trial did better than expected with a 64% return on the questionnaire, which left Asthmatx with a tighter margin than was needed to demonstrate non-inferiority.

Castro noted that FDA asked for a post-study evaluation of data from Brazilian sites, which tweaked the numbers for Australian and U.S. sites into a significantly better score. However, he noted that the data indicated there was "no significant difference" in outcomes in Brazil. However, Castro also pointed out that "maintenance asthma medications were provided free of charge" to the Brazilian enrollees, which may have driven greater compliance with post-procedural pharmacological medication usage.

Outside of Brazil, Castro noted, "we did meet the primary endpoint," and he asserted, "the totality of the evidence is that this treatment is safe and effective." He also argued that there is an unmet need because of the continued impairment despite pharmacological regimes.

Perhaps the greatest factor in favor of the AIR 2 data was the promising outcome of secondary efficacy measures. Patients who were treated with ablation experienced a 32% drop in severe exacerbations of their condition, and also lost only 1.32 days of work or school in the first year on average, a drop of almost two thirds compared to the patients on the sham, who lost an average of 3.92 days in that first year. The control patients were about six times more likely to need a trip to the emergency room to deal with an asthma attack.

Several patients gave their views of the device during the open public hearing, and most of them came to tears during their testimony. "I feel like I'm living with a time bomb," which could go off without warning, one patient said. Another patient testified, "before the procedure, the [influenza] bug would have put me in the hospital." He also said that "this treatment is not experimental; it works."

During panel discussions, several panel members noted that the trial missed the mark on the primary endpoint and panel chairman David Birnbach, MD, of the University of Miami School of Medicine (Miami) concluded: "the consensus of opinion is that the endpoint was not met, but several of the panelists believe that the other data were very impressive."

As for the differences between national outcomes, one panelist observed, "I would be a lot more bothered" if the U.S. generated all the outlier data, and another made the point that the successful data are for "the U.S. population and we have approval based" on that population. Birnbach summarized that "the vast majority of the panel members felt [the variance by geography] was relevant," but noted that a statistician "felt it may fit with the variation" that is often seen in trials. He also noted the effect on compliance engendered by the free medications given to patients in Brazil.

The panel voted 6-1 for approvability with a number of conditions, including that the firm set up a registry for all patients tracking durability of effect. There was some discussion of tracking patients for as long as 15 years, but the firm's proposal of a five-year follow-up held. The panel recommended further that the treatment not be used on patients with impaired coagulation

Glen French, president/CEO of the firm, told Medical Device Daily after the hearing that the company chose Brazil and Australia as study sites because the difference in seasons "would take seasonality out of the equation." He also noted that healthcare in the participating Brazilian hospitals is not reflective of second-rate care. "We wanted first-world healthcare," he said, which the Brazilian hospitals offered.

As for reimbursement, French noted that the firm is pursuing talks with "both public and private payers," although the population in question is generally not Medicare eligible. "We've had lots of interactions with private payers, which is unusual," he said, noting that payers see this population as "very expensive," thanks to all the trips to hospitals and emergency rooms.

Mark McCarty, 703-268-5690