Medical Device Daily Washington Editor

WASHINGTON — Some industry observers are probably of the opinion that FDA advisory panels have become more demanding of applications for 510(k)s and PMAs over the past year or two, and a recent experience by one firm, Neuronetics (Malvern, Pennsylvania) might serve to buttress that perception.

Despite coming very close to a statistically significant demonstration of equivalent efficacy in addition to superior safety to the predicate device, the panel, without formally voting, gave the sponsor’s electromagnetic treatment for depression a thumbs down even though it would replace a therapeutic route that requires anesthesia and intubation.

The NeuroStar is a device that seats the patient in a chair resembling a dentist’s chair and uses an electromagnetic field as an alternative to the direct application of electricity required for electro-convulsive therapy (ECT). The device makes use of an electronic coil that is boosted by a magnetic resonance field, which is applied to the forehead of the patient for 40-minute intervals. The electromagnetic field influences the pre-frontal cortex primarily, and the mechanism of action is thought to be dependent on the ability of the pre-frontal cortex to then stimulate the limbic system, which consists of the hypothalamus, the hippocampus and the amygdala. Side effects are said to include headaches, pain, muscle-twitching and skin discomfort, but this procedure does not require anesthesia and intubation, unlike ECT.

Neuronetics filed the application with ECT serving as the predicate device despite the difference in energy type and made the case that because of the substantially lower risk of side effects, such as loss of memory, headaches and burns, that the NeuroStar should not be held to the same standard of efficacy as ECT.

The argument did not hold up in the minds of the panelists, but the agency, as always, is not bound by the panel’s decision.

The chair of the advisory panel, Thomas Brott, a professor of neurology at the Mayo Clinic (Jacksonville, Florida), argued that any clinical effect “was perhaps marginal, borderline, questionable,” adding that “[p]erhaps a reasonable person could ask whether there was an effect at all.”

One of those appearing at the meeting was Steven Zatuchni of Wynnewood, Pennsylvania, who told the panel that NeuroStar was the first therapeutic intervention that had shown any effect in the 15 years he has dealt with depression.

“I lived in my own world, excluded my family and slept up to 18 hours a day,” he said, adding that within a week of starting on the clinical trial, “I made measurable progress toward a cure that came within a few weeks and had no side effects.” However, he had to resume drug treatment after his participation in the trial ended, and he relapsed, becoming “as lethargic as I had been before.” Several other patients offered similar testimonials, to no apparent avail.

Peter Anastasiou the vice president of marketing at Neuronetics, told Medical Device Daily that despite claims to the contrary, “[o]ur view is that we’ve clearly demonstrated efficacy, and one of the things that the panel may not have fully understood was the population we were studying.” People who had not responded to previous treatments, “and on common measures of depression, we showed statistically significantly efficacy.”

Anastasiou said that the primary outcome was not statistically better than the placebo provided by a sham device, but he also said that with an achieved level of significance of .057, “we barely missed the statistical cutoff” on the primary endpoint, which was “acute safety and effectiveness” at relieving depression at four weeks. The trial, however, called for six weeks of treatment.

One of the complaints voiced by the panel was that 156 of the subjects who enrolled in the control arm migrated to the study article, which Anastasiou said was driven by the fact that these patients had been previously treated for depression and “we wanted to give the patients who were randomized to sham a chance to go to the NeuroStar.” He noted that all patients were blinded the entire time, but after four weeks, they had the option of moving out of the control arm if they felt they were making no progress.

Anastasiou said that perhaps the panel might not have fully appreciated that “[w]e studied a group of patients that were not responsive to previous therapies and had a resilient form of depression, and this is not what is typically studied.” Most studies of depression treatments take on first-line patients, and the patients who were enrolled in the clinical trials for the NeuroStar had experienced no resolution of their depression after one to four different treatment regimes in their current depressive episode.

“To expect huge numbers [in such a population] in terms of efficacy is unreasonable,” he remarked.

At present, the company does not expect to make any serious changes in its application, but is “look[ing] forward to working with the FDA to make the device available,” according to Anastasiou. He noted that the firm had not initially or subsequently thought about putting the NeuroStar through the PMA process, which would have generated a larger data set that might serve as a rationale for reimbursement. “We considered all options and we made the one we felt was best for us,” he commented, adding that the Centers for Medicare and Medicaid Services (CMS) is aware of “a fairly strong track record of transcranial magnetic stimulation for efficacy and therapy.”

“We’re very confident in our data and that we showed efficacy on many common measures,” Anastasiou insisted, stating further that “CMS and other audiences will find the data compelling.”