The FDA Transcranial Magnetic Stimulation Approval Process

Psychiatry Online reported in 2008 that the Food and Drug Administration (FDA) approved the first transcranial magnetic stimulation (TMS) device for the treatment of medication-resistant depression. The device is manufactured by Neuronetics Inc. The device is called NeuroStar TMS Therapy system. The medical device is a daily monotherapy for adults with major depressive disorder – and may be recommended for patients who have not responded to “at least one course of antidepressant treatment with an adequate dosage and duration.”

What is transcranial magnetic stimulation (TMS)?

According to the Mayo Clinic, the FDA-approved TMS:

• When other depression treatments have not worked
• For other conditions too including obsessive-compulsive disorder (OCD), migraines and to help people stop smoking when standard treatments haven’t worked well.

Other uses for TMS are being researched. When TMS is used for depression, OCD, and smoking cessation; the treatment requires the use of “repeated magnetic pulses, so it’s called repetitive TMS or rTMS.”

The TMS device uses repeat “high-frequency magnetic pulses at a specific location outside the cranium to provoke electrical currents inside the patient’s brain, thus activating the neurons in the prefrontal cortex.”  The procedure is conducted in an outpatient setting. It is considered a noninvasive and painless treatment. No anesthesia or sedation is required. The patient stays awake during the procedures which last for about 40 minutes. The stimulation process “delivers 3,000 pulses per session.”

How does TMS work?

According to the Mayo Clinic,

“During an rTMS session for depression, an electromagnetic coil is placed against the scalp of your head. This coil delivers magnetic pulses that stimulate nerve cells in the region of your brain involved in mood control and depression. It’s thought to activate regions of the brain that have decreased activity during depression.

Although the biology of why TMS works isn’t completely understood, the stimulation appears to affect how the brain is working. It seems to ease depression symptoms and improve mood.

There are different ways to perform TMS. Methods may change as experts learn more about the most effective ways to perform treatments.”

TMS treatment for depression

Psychiatry Online stated that the approved TMS device was tested in a “randomized, sham-controlled, double-blind clinical trial of the TMS device conducted from January 2004 to August 2005. 300 patients with major depression who had not responded to prior medications (had failed a median of four treatments of antidepressant therapy) were separated into people who either received an active or a sham stimulation – each day for six weeks.”

The success of the study was published in the December 1, 2007, Biological Psychiatry by John O’Reardon, M.D., and colleagues. Some of the patients in the clinical trial continued with “active, open-label treatment for up to 24 weeks,” with few reported adverse effects. None of the patients died or had seizures from the trial and none suffered memory loss or cognitive changes. Less than five percent of the participants who continued the treatment – discontinued the treatment due to adverse events. The noted adverse side effects included one patient who suffered left-sided facial numbness and two patients who suffered first-degree burns and pain – due to device malfunction.

The TMS device “stimulates a specific area of the brain—the left dorsolateral prefrontal cortex.” A professor of clinical psychiatry at Columbia University and the New York State Psychiatric Institute (and one of the investigators in the Neuronetics trials) stated that stimulation over time is “likely to lead to beneficial changes in other regions involved in depression.” The goal of the studies of TMS was to hopefully show that the treatment will be a second option after pharmacotherapy but before electroconvulsive therapy (ECT) which requires anesthesia or sedation.

The FDA review process

In January 2007, “an advisory panel told the FDA that the device is safe, but that its efficacy may not be “substantially equivalent” to ECT.” Because the “substantially equivalent to an approved treatment test” could not be met, the TMS treatment could not be approved for a premarket 510(K) notification.

501(K) is an accelerated market-approval process in which the applicant needs only to prove that a device is “substantially equivalent” to another marketed device in safety and efficacy. 

The FDA requested the clinical trial data described above and issued clearance/approval in 2008.

Psychiatry Online added that the availability of TMS treatment is not indicated after a patient fails one course of drug therapy (with a proper dosage and duration) because many patients, due to issues of drug tolerance, often have to try “several antidepressant drugs for months before completing one course of pharmacotherapy at minimum effective dose and duration.”

TMS treatment for OCD

On August 17, 2018, the US FDA permitted the marketing of another TMS treatment. “the Brainsway Deep Transcranial Magnetic Stimulation System for treatment of obsessive-compulsive disorder (OCD).”

According to the director of the Division of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health, Transcranial Magnetic Stimulation has shown the potential to help patients with depression and headaches. The August 17, 2018 marketing authorization authorizes the use of TMS to treat OCD for patients who have not responded well to traditional remedies.

OCD affects about one percent of the US population. OCD is a long-lasting disorder where the patient “has uncontrollable, reoccurring thoughts and behaviors that a person feels the urge to repeat over and over.” While other treatments help many patients, some patients fail to respond to those treatments.

As discussed, the FDA granted “marketing of TMS as a treatment for major depression in 2008.” TMS was granted marketing approval for treating certain migraine headache pains in 2013.

Before granting approval to market TMS as a treatment for OCD, the FDA had to review a clinical study of the effectiveness of the treatment and the scope of the adverse treatments – similar to the initial approval of TMS for depression as discussed above. A review of clinical studies and adverse effects is required when a device manufacturer or provider cannot show that the devices is substantially equivalent to an approved FDA device.

• The clinical study. The FDA reviewed a study of 100 patients where 49 OCD patients received treatment with the Brainsway device and 51 patients were treated with a “sham” device. Patients who were receiving medical treatments for OCD were kept on those treatments at the same dosage throughout the study. The study showed improvement in 38 percent of patients who used the Brainsway device and 11 percent who used the sham device.
• The adverse effects. About 35-37 percent of the patients reported headaches while using the Brainsway device and the sham device.

“No serious adverse reactions related to the Brainsway device were reported. Other adverse reactions, such as application site pain or discomfort, jaw pain, facial pain, muscle pain, spasm or twitching, and neck pain, were reported as either mild or moderate and resolved shortly after treatment.”

There were some contraindications for the use of the Brainsway device – in patients with cochlear implants, bullet fragments, jewelry, hair barrettes, and other objects in or near the head. Patients do need to wear earplugs during the treatments. “Patients with a history of seizures should discuss their history with their health care provider before receiving the device.”

The FDA review standard for the Brainsway device

“The FDA reviewed the Brainsway device through the de novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no legally marketed predicate device to which the device can claim substantial equivalence.”

The FDA, a US DHHS agency, works to protect the public health

“by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco product.”

Additional FDA criteria for marketing TMS and rTMS devices

The FDA, in 2011, prepared a guidance document for Repetitive Transcranial Magnetic Stimulation (rTMS) systems. A few of the key items in the document include the following:

• The document was developed as a “special controls guidance to support the classification of Repetitive Transcranial Magnetic Stimulation (r TMS) systems for the treatment of Major Depressive Disorder (MDD) into class II (special controls).”
• As discussed, an “rTMS system is an electromagnetic device that non-invasively delivers a rapidly pulsed magnetic field to the cerebral cortex in order to activate neurons within a limited volume without inducing a seizure.”

“FDA believes that special controls, when combined with the general controls, will be sufficient to provide reasonable assurance of the safety and effectiveness of rTMS systems for the treatment of MDD in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.”

• Individuals and companies who intend to market an rTMS system based on a prior FDA marketing approval must:
  • Comply with the “general controls” of the federal Food, Drug, and Cosmetic Act (the FD&C Act) – including the premarket notification requirements
  • “Address the specific risks to health associated with repetitive transcranial magnetic stimulation systems identified in this guidance.”
  • “Obtain a substantial equivalence determination from FDA prior to marketing the device.”

FDA has identified the health risks generally associated with the use of the rTMS systems discussed in the guidance document. The guidance document has specific recommendations for how any clinical trials should be conducted, what adverse effects should be evaluated, and many other criteria.

Healthcare compliance issues for noninvasive treatments like TMS

The FDA has approved Transcranial Magnetic Stimulation (TMS) treatments for several health disorders including depression and obsessive-compulsive disorder (OCD) – when other medical treatments fail. The FDA generally requires that clinical studies confirm the effectiveness of the medical device and the adverse effects. Approval may be based on these clinical studies and/or a showing that the device is substantially equivalent to a pre-approved FDA medical device.

Medical device manufacturers, physicians, and psychiatrists should contact Cohen Healthcare Law Group, PC to discuss FDA approval of rTMS for the treatment of various illnesses. Our experienced healthcare attorneys advise physicians and medical practices about healthcare compliance laws and regulations.