The Food and Drug Administration's Neurological Devices Panel recommended
in late January against approval of a transcranial magnetic stimulation (rTMS)
device for treatment of major depression. Although panel members believed the
device to be safe, they questioned whether any benefit from the treatment was
The device, called the NeuroStar TMS Therapy System, is manufactured by
In a statement the company released the day after the hearing, Neuronetics
President and CEO Bruce Shook said, "We are confident in the efficacy of
our NeuroStar TMS Therapy system, and we look forward to working with the FDA
to resolve any remaining questions [the agency has regarding
Neuronetics had sought FDA approval of the rTMS device through what is
called a "510(k) submission." A 510(k) asks the FDA to approve a
device on the basis that it "is substantially equivalent" to a"
predicate device"—that is, a similar device that is already
approved for marketing and use in the same or similar clinical
Neuronetics asserted in its 510(k) application that the rTMS device"
is substantially equivalent" to electroconvulsive therapy (ECT)
devices for treatment of major depressive disorder, although rTMS and ECT
devices have "technological differences that include modifications in
design, materials, and in energy source."
FDA neurophysiologist and group lab leader Victor Krauthamer, Ph.D.,
reminded panel members that the regulations governing a 510(k) submission
require that any technological differences "pose no new types of
questions regarding safety and effectiveness, and the package submitted by the
sponsor must contain clinical evidence of a comparable risk-to-benefit
Indeed, the comparison of efficacy between the TMS system and ECT would
prove to be Neuronetics' downfall.
The company submitted data from three clinical trials that it believed
demonstrated that the rTMS system met the regulatory requirements of a 510(k)
Judy Ways, Ph.D., Neuronetics' vice president for regulatory affairs and
quality assurance, told the panel that it is important to remember that a
510(k) submission "does not require equal risk and equal benefit. The
new device could be safer but less effective than the predicate device, or the
new device could be less safe but more effective. The NeuroStar risk/benefit
profile compares quite favorably to ECT."
"NeuroStar safety is superior to ECT," Ways told the panel."
NeuroStar is effective, but less so than ECT. However, NeuroStar
benefit is sustained and at least as durable as ECT."
Mark Demitrack, M.D., the company's chief medical officer, described
Neuronetics' Study 101. This was randomized, double-blind, sham-controlled
trial lasting six weeks and included 325 patients, 155 of whom were randomly
assigned to receive active rTMS treatments. The remaining 146 patients were
randomly assigned to go through a "sham TMS" treatment: the device
had inactive, nonmagnetic treatment coils.
The change in the total score on the Montgomery-Asberg Depression Rating
Scale (MADRS) was defined as the a priori primary outcome measure. Nine
secondary outcomes were also measured, including the Hamilton Depression
Rating Scale for Depression (HamD).
At both four and six weeks, patients in the active and sham groups showed
significant improvement; however, the difference between the two groups just
missed meeting the test of statistical significance, where a p-value must be
0.05 or smaller.
At four weeks the difference between the two groups had a p-value of 0.057,
and at six weeks the p-value was 0.058. Thus, Study 101 was judged a failed
trial—it did not support the hypothesis favoring the efficacy of
The majority of the secondary outcomes measured in Study 101 supported the
efficacy of rTMS and met that magical threshold of statistical significance
with p-values much less than 0.05. Yet many panel members were unable to move
beyond the failure of the study's primary outcome to achieve statistical
significance, even after an outside expert in biomedical statistics told the
panel he agreed with the panel's own statistical expert that "the
difference between a p-value of 0.057 and 0.050 is virtually clinically
undistinguishable." Both statistical experts appeared to believe the
p-value was close enough to not represent a concern.
The other two trials on which Neuronetics presented data were an open-label
crossover study and a maintenance-of-effect study.
Michael Thase, M.D., a professor of psychiatry at the University of
Pennsylvania, consulted with Neuronetics on development of rTMS and testified
on behalf of the company at the hearing. In a follow-up telephone interview
with Psychiatric News, he said that "the therapeutic effect
seen with rTMS is real, but it is relatively small in comparison to the effect
sizes traditionally seen with ECT."
Nonetheless, he continued, "the effect size demonstrated with rTMS is
roughly equivalent to, if not a bit larger than, the average effect size seen
with all of the newer antidepressant medications currently on the
Thase emphasized that ECT is "significantly better than rTMS, but it
comes with a price—substantial and clinically significant risks that
limit its use. rTMS, on the other hand, is much safer and just as effective as
In the end, Thase said, the requirement to compare rTMS to ECT proved to be
a big hurdle.
"ECT and rTMS are simply two different treatments," Thase said,"
with different risk-benefit profiles."
Neuronetics' chief medical officer, Mark Demitrack, M.D., told
Psychiatric News, "I don't think there was any doubt [in panel
members' minds] that the safety profile was far superior with rTMS. But when
you try to balance the safety-efficacy profile, there's very little to help
the panel—in fact, there's no solid quantitative guidance on how the
panel should do that.
"I would hope, however, that [panel members] did not come away from
this meeting with the idea that rTMS does not work," Demitrack
concluded. "While the review was mixed, from my perspective that was
good news. Given the fact that this is a new device, not a drug, and it is
very different from anything they've seen before, the panel was trying to
figure out what the pattern of benefits really is."
While the FDA is not bound to follow its advisory panel's recommendations,
traditionally the agency does follow the experts' lead. No timetable is set in
stone, however, historically the agency has made final decisions on
applications for approval within three to six months following a public
"Overall," Demitrack said, "I feel confident that rTMS
will ultimately make its way to clinical practice."
Materials presented at the Neurological Devices Panel meeting
regarding rTMS arepostedat<www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4273b1_00-index.htm>.▪