From Ritalin to brain implants: How the FDA is fast-tracking the devices of the future
In part one of this article, we described eTNS (external Trigeminal Nerve Stimulation), which has been approved by the FDA for the treatment of ADHD. NeuroSigma, which markets its Monarch eTNS System, conducted just two trials on the device, one of which was a feasibility study with very mixed results. Nonetheless, the FDA gave a green light to further eTNS research and then approved the device after receiving the results of a second trial in which just 59 children were enrolled.
FDA approval after a 4-week study
Years ago, the FDA demanded multiple trial results before approving drugs and devices. In recent years, the results of just two trials have generally been enough to satisfy federal regulators. With Monarch eTNS, however, the FDA was happy with just one trial, even though only 31 children were exposed to the device.
The trial was, unlike the feasibility study, double-blinded and sham-controlled (with a sham device used in the control group which looked like the genuine device but emitted no electric pulses). Also unlike the feasibility study, this trial lasted just 4 weeks (as opposed to 8). Neither NeuroSigma nor the FDA published the reasons for conducting the study over such a short period of time.
eTNS helped everyone — even the kids in the placebo group
While the feasibility study was conducted on children deemed to have “moderate to severe” ADHD, the reports on this study make no mention of how severe or otherwise the children’s ADHD was. However, from the graph showing decline in their ADHD scores, it is clear that they had no more than moderate ADHD, as they started off with around 33 points on a 54-point scale.
As the graph below shows, improvement was seen quickly in both groups and was sustained throughout the trial, even in the sham group. The researchers do not suggest any reason why this should be.
The results were, however, deemed clinically significant.
Adverse events? Depends who you ask
During the four weeks of the trial, the children enrolled reported many different side effects which were categorized as either “mild” or “moderate.” The report does not mention who did the categorization.
The FDA also states that,
No serious adverse events were associated with use of the device [emphasis added].
It is perhaps safe to assume that, given this choice of words, there were indeed serious adverse events — however, the researchers decided that the Monarch eTNS device was not responsible for them. At any rate, they are not listed.
Side effects? They don’t make sense
Nonetheless, the FDA did highlight side effects “observed with eTNS” which included,
... drowsiness, increased appetite, trouble sleeping, teeth clenching, headache, and fatigue...
The FDA report doesn’t detail the extent of these side effects, but the actual trial report (here) compares the active versus sham group with regard to height, weight, pulse, and blood pressure. Significant differences were found in the weight and pulse categories, with children in the active group gaining on average 2 pounds over the 4 weeks of the study (as opposed to 10 ounces in the sham group). Pulse rates went up from 71.7 on average to 81.8 bpm in the active group, while rates dropped on average in the sham group.
In the study, the researchers appear surprised at this significant rise in pulse rates, admitting that based on their (clearly limited) understanding of the way eTNS works, they would have expected the reverse to occur:
The potential significance of observed increased heart rate with active TNS remains unclear. Prior acute studies of TNS have revealed both increases and decreases in pulse. As with the vagus nerve, TNS is known to elicit parasympathetic activity, which is expected to result in pulse decreases or bradycardia.
So effective that most users dropped out of the study
Under the heading, “A safety profile you can trust,” NeuroSigma describes several side effects associated with eTNS (those mentioned by the FDA) and stresses the “no serious adverse events have been associated...” claim.
It then goes on to describe the system as having “proven efficacy.”
However, what NeuroSigma doesn’t mention (though the FDA trial summary does) is that some trial volunteers were invited to continue treatment for an entire year — and most of them dropped out way before the year was up.
This is even more remarkable given that the option was only open to children who experienced “clinically meaningful improvement” during the study. Furthermore, children in the sham group (placebo) were also allowed to participate at this stage and join the active group, setting up eTNS for successful trial results, given that a) only those who had benefited were included and b) those who were clearly susceptible to feeling benefit even when they weren’t being treated were also allowed to join.
18 children were still in the trial at 3 months. By 6 months, 10 had dropped out. At 9 months, there were just 6 children left. At 12 months, only 3 children were left using eTNS (2 from the original active group and 1 from the sham group).
If eTNS was so effective (not to mention safe), why did 15 out of 18 children stop using it?
Children getting tangled in the wires
NeuroSigma also paid no attention to the three children for whom some of the results had to be omitted in the original controlled study, although the reason why is noted in the trial report:
... data for 3 participants were excluded due to excessive movement artifact...
In plain language, what this means is that the kids moved around too much in their sleep, which affected the accuracy of the readings.
In another study investigating eTNS, following 4 Danish children, the same concern arose, when one of them,
... got tangled in the cables. This required that the parents often checked him at night.
ADHD, or just tired?
This Danish study did find an improvement in ADHD symptoms among the children tested. However, they also observed that the eTNS device appeared to have improved the children's sleep patterns and quality, and suggested that improved sleep alone could have been responsible for their changed behavior.
While the researchers did not follow up on their observation, researchers in other countries have noted the connection between a diagnosis of ADHD and sleep disturbances, and have suggested that when the underlying sleep disorder is treated, the “ADHD” tends to go away.
However, given that there are no objective tests for ADHD — neither neurological, nor biological, nor genetic — it is easy to ignore the results of such studies. The incentive to do so is of course considerable, because, unlike treated sleep disorders, treated ADHD tends to be a years-long affair, with associated years-long profits for the makers of the drugs or devices “treating” it.
FDA fast-track for more electric shock devices
The future for drugs is probably assured, even though NeuroSigma’s Chief Medical Officer, Dr. Ian Cook, has suggested that the Monarch eTNS could one day supersede drug treatment:
Given emerging shortages of leading ADHD medications in the United States, the launch of a non-drug alternative to potentially addictive pharmaceutical stimulants is even more imperative in expanding long-term therapeutic options...
The future for devices may be far more rosy, and things are only just getting started. In fact, the FDA seems to be giving the nod to device manufacturers to go full speed ahead. As regulators note, Monarch eTNS received preferential treatment:
The FDA reviewed the Monarch eTNS System through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type. This action creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) premarket process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a predicate device [emphasis added].
This is similar to the way in which the FDA authorized the so-called bivalent COVID vaccines, relying on “substantial equivalence” to the original shots, plus a nominal study on a few mice.
A market of millions of people…
The FDA is also encouraging NeuroSigma despite the considerable cost of the device and the disposable patches. The pulse emitter alone costs $1,000 and a month’s supply of patches costs $100. However, the company has announced a co-pay program whereby children with insurance and an ADHD diagnosis would only pay $40 per month for patches.
For NeuroSigma, even offering a steep discount would be worth it, once it has access to the huge ADHD market. As its president, Dr. Colin Kealy, stated,
NeuroSigma’s mission is to facilitate access to eTNS therapy for the millions of children worldwide struggling with ADHD. Our new Pediatric Care Co-Pay Program is an important milestone towards achieving this goal and will significantly increase the affordability of our therapy for eligible patients and their caregivers in the United States.
… and billions of dollars
According to a report on GlobalData’s Medical Intelligence Center, the broader field of wearable technology is forecast to become a huge $291 billion industry by 2030, with healthcare identified as a key market for wearable devices. NeuroSigma clearly intends to be part of this, not only with its Monarch eTNS System, but also with an entire “digital health platform,” as its director, Thomas Paschall, stated after the Monarch system gained FDA approval:
We anticipate NeuroSigma announcing additional global partnerships and continuing to build a world class dataset for ADHD and other indications, such as drug resistant epilepsy and autism spectrum disorder.
Today, electrodes — tomorrow, implants
NeuroSigma has already begun testing eTNS for “treatment-resistant” epilepsy (as well as for depression and PTSD in veterans). They are not the first to be testing eTNS for epilepsy, however — previous studies have returned mixed results on its efficacy, with around two-thirds of trial participants dropping out within the first few years of use.
Nonetheless, an article in the European Journal of Epilepsy forecasts a bright future for device-based treatment, even suggesting that implanting devices could be the treatment mode of the future:
In patients with a good response to eTNS an implantable device (under development) could be placed subcutaneously. However, larger controlled studies are required in order to establish the place of eTNS in the treatment of epilepsy.
To summarize:
The FDA has given the green light to electric shock treatment of young children, based on a four-week controlled study with less than 60 children enrolled, and claims that its approval of Monarch eTNS,
... reflects our deep commitment to working with device manufacturers to advance the development of pediatric medical devices so that children have access to innovative, safe and effective medical devices that meet their unique needs.
All this, while admitting that,
... the long-term effects of using the Monarch eTNS System are unknown...
Disclaimer: The information contained in this article is for educational and information purposes only and is not intended as health, medical, financial or legal advice. Always consult a physician, lawyer or other qualified professional regarding any questions you may have about a medical condition, health objectives or legal or financial issues.
