Medical Device Daily Washington Editor

GAITHERSBURG, Maryland – One of the things that Emphasys (Redwood City, California) had going for it at an FDA advisory panel last Friday was that it presented a first-of-a-kind device, the Zephyr endobronchial valve system, which is designed to deal with a poorly met need, namely grade III and IV emphysema.

On the other hand, one of the things Emphasys had going against it was that it presented a first-of-a-kind device with too little long-term data to demonstrate enough efficacy to nudge the advisory committee into voting for approvability.

Despite meeting the two primary effectiveness endpoints per one of the analyses of the trial data, the device earned an 11-2 vote against approvability, an outcome decided by what panelists saw as a middling effect on emphysema outcomes. This question loomed large enough that the panel chairman, David Birnbach, MD, of the University of Miami School of Medicine (Miami) summarized the panel's view that "we are not sure there is any clinical significance" to the data rendered by the study.

In the company's morning presentation to the Anesthesiology and Respiratory Devices advisory committee, Gerard Criner, MD, a professor of medicine at Temple University (Philadelphia), reminded panelists that emphysema is "a progressively debilitating disorder" that affects 12 million. "The only medical treatment shown to be effective is oxygen therapy" and inhaled corticosteroids for grade III and IV patients. "Because of the high mortality despite medical treatment," surgeons have sometimes opted for lung volume reduction surgery (LVRS).

LVRS became the object of a minor medical stampede in the mid-1990s, but the Centers for Medicare & Medicaid Services (CMS) suspended payment for the procedure in 1996 because outcomes were seen as not demonstrably better than medical treatment, which prompted the conduct of the National Emphysema Treatment Trial (NETT) by the National Heart, Lung and Blood Institute.

CMS currently pays for LVRS, but with several restrictions on patient selection.

Armin Ernst, MD, a pulmonologist at Beth Israel Deaconess Medical Center (Boston), noted that the Zephyr is "an implantable one-way valve" that is "removable and reversible." The device, which is constructed partly of struts that are reminiscent of a vascular stent, allows air to drain out of the area of the lung behind it, but does not allow air back in. This mechanism of action is intended to reduce to volume of the affected area of the lung, which, like LVRS, reduces overall lung volume and normalizes the geometry of the interface between the lungs and the diaphragm.

As for the pivotal trial for the Zephyr – dubbed the Valve for Emphysema PalliatioN Trial (VENT) – Ernst noted that FDA approved the design in 2003 and that "an FDA panel recommended that the target population should be similar to [that found in] NETT." VENT, he said, was a prospective randomized controlled trial at 31 centers enrolling 321 patients. The two primary outcomes were improvement in forced expiratory volume (FEV) via spirometry and in the six-minute walk test at six months.

Ernst said that the trial did show some device expectoration and migration, but said, "This is probably more an operator-dependent issue." The study subjects experienced eight expectorations and nine migrations after a year, a situation Ernst said was dealt with largely via better surgeon training.

He also said the company added a depth marker to the catheter to help guide placement. "This is an event that with increasing experience is becoming more and more rare," Ernst asserted.

Still, rehospitalizations were higher in the treatment group (39.7% vs. 25.3%), mostly due to exacerbations of those patients with chronic obstructive pulmonary disorder (COPD), a blend of chronic bronchitis and emphysema.

In conclusion, Ernst said, "there's definitely no increased mortality in the treatment arm," and periprocedural adverse events "were minor and expected." Only two serious adverse events were statistically significant at one year, which were COPD exacerbation and hemoptysis (coughing up blood).

Alvin van Orden, PhD, a biostatistician at FDA, told the panel that the device achieved the two primary endpoints in the intent-to-treat population, but not in an analysis that included patients whose participation violated the protocol. He said 62 patients "did not meet the inclusion/exclusion criteria" and that nine patients "took medication in violation of the protocol."

van Orden also noted that data from a European arm of the study were not pooled with the U.S. data, part of a change to the statistical analysis plan to which FDA had agreed.

In addressing patients whose conduct violated the study protocol and some whose follow-up appointments were outside the protocol's term, most panelists indicated they were not overly concerned, and one panelist reminded the others "these patients are desperate." Birnbach summarized the panel's opinion that "they don't appear to be a major issue."

After some back-and-forth on the question of efficacy, Birnbach said "the panel believed that there is some promising data ... but there did not [appear] to be a huge difference" between controls and study subjects. "We are not sure there is any clinical significance," he said, adding that panelists saw "some troubling information that this may not [render] a permanent effect" because patients tended to do worse on the six-minute walk at one year than at six months. Safety was not seen as an issue, but the panel voted 11-2 to vote against approvability based on the modest efficacy data.

John McCutcheon, president/CEO of Emphasys, told Medical Device Daily that the company will "need time to re-strategize, but our current thinking is to find out what FDA will want" and go from there. He said options include building a new trial and increasing enrollment on the existing one. The latter option is less costly, but "it could be a hybrid" of the two, he said.

McCutcheon said he was "very surprised and disappointed" at the outcome. "I thought our clinicians did a remarkable job delivering the message" and "with a different mix or a different panel, it might have gone the other way."

He indicated few concerns about capitalizing further efforts. "We still have venture investors" who "remain committed to seeing this through."

McCutcheon also indicated optimism about the company's and the product's future. "I think we'll ultimately be approved. It's just a matter of time and finding the right path."