Clinical Trials for Neurotechnologies
In a recent study, researchers implanted a multielectrode array in the brain of a stroke patient with paralysis and inability to speak. They recorded cerebral cortical activity while the individual attempted to speak. Using computational models, they were able to decode full sentences in real time as the participant attempted to say them. Clinical studies like this one have the potential to dramatically improve quality of life for people suffering from debilitating conditions, and they are an early step in the process of developing and commercializing new neurotechnologies.
In the same year that this early stage, one person study was published, several other devices were successful on the opposite end of the spectrum: they achieved full approval from the Food & Drug Administration (FDA). These included an electromyography-based seizure monitor, a remote neurostimulator for migraine treatment, a spinal cord stimulator to treat chronic pain, a deep brain stimulator to treat tremor and Parkinson disease, and a focused ultrasound, also for the treatment of Parkinson disease.
How did these devices make it across the finish line and, more generally, what is the clinical trial process that many neurotechnologies and other medical devices must follow to achieve regulatory approval? In this article, we present an overview of this process, we discuss several high-profile examples, and we present challenges and opportunities for conducting clinical trials in neurotech.
A Clinical Trials Primer
Clinical trials are research studies that evaluate the effectiveness and safety of a medical product to justify its use in humans. Clinical testing for medical devices can include many types of scientific evidence, such as randomized controlled trials, studies without matched controls, and well-documented case histories. The FDA needs evidence that a clinical trial design is scientifically sound and that the potential benefits to patients outweigh potential risks. Initiating a clinical trial requires regulatory approval, and manufacturers must consider a variety of factors including appropriate patient selection, a treatment regimen, related surgical procedures and care, clear efficacy and safety outcomes, a statistical analysis plan, and a plan for adverse safety events. Notably, clinical trials are typically required for high-risk devices and those that are truly novel where there is insufficient data about the safety or the benefits, but they are not always required for low-risk devices with established precedents.
Like all medical products in the United States, neurotech devices are regulated by the FDA. Within the FDA, the Center for Devices and Radiological Health (CDRH) is responsible for reviewing devices that are considered medium- to high-risk. An early step in the review process is “first in human” testing, which requires researchers to obtain an Investigational Device Exemption (IDE). This step engages the FDA in discussions about safety and provides a pathway for in-human study. Results from early studies will dictate the appropriate regulatory pathway, which considers the potential risk, the similarity of the new device to others already approved, and the number of people with the condition that the device is intended to treat.
The Neurology Program in the CDRH helps ensure patient access to innovative neurotechnologies that are safe and effective. The neurological device space is growing fast, particularly in surgical devices. Clinical neurological devices face significant scrutiny with testing for safety and effectiveness, but the CDRH has published excellent resources to describe its risk assessment, regulatory pathways, public engagement, and organizational structure.
The FDA has also issued specific new guidelines for regulating brain-computer interface (BCI) technology. The guidelines intend to help startups navigate the clinical trials process. In fact, the recent emergence of many startups may have prompted the FDA to issue guidance, since part of the agency’s mission is to see that devices get to market quickly and safely. The guidance document provides recommendations for non-clinical testing and for the design of feasibility and pivotal clinical trials for implanted BCI devices.
It’s worth noting that current approaches for generating research evidence for neurotechnology are still often based on clinical trial practices designed for pharmaceuticals. However, some argue that these approaches are not suitable for technology-based interventions. They advocate for alternative approaches to generating evidence. For example, the Framework for Accelerated and Systematic Technology-based intervention development and Evaluation Research (FASTER) is informed by innovation design processes and concepts. For devices, clinical trials can sometimes be completed with just a handful of patients for feasibility trials and just a couple of hundred for pivotal trials.
Recent Headlines
The clinical trials landscape is vast. ClinicalTrials.gov reports that as of March 2023, there are over 46,000 registered device studies in their database. WIKISTIM, a database of primary clinical and experimental data reported in the neuromodulation literature, includes over 7,000 deep brain stimulation studies and over 3,000 spinal cord stimulation studies. Nonetheless, a few recent neurotech trials are worth noting.
Initial feasibility trials
Feasibility trials are proof-of-concept studies to establish safety in humans and initial evidence of effectiveness. Nearly two decades after its NeuroPort Array gained the FDA’s first approval for an implanted electrode panel to send brain signals to a computer, Blackrock Neurotech’s newest BCI is the MoveAgain system, which detects signals from the brain of paralyzed patients and decodes their intent to control computers and other devices. The BCI relies on Blackrock’s existing electrode array technology.
Blackrock will be competing against Synchron, a neurotech startup, to become the first to receive approval for an implanted BCI. The FDA granted the go-ahead to Synchron to conduct a feasibility trial to test its neural implant in human paralysis patients. Synchron’s Stentrode device could enable the treatment of conditions ranging from Parkinson’s disease to paralysis. The Stentrode device is inserted in the jugular vein and routed to the brain to gather neurological signals that are then used to control a computer. The device is described as minimally-invasive and is based on stents and other devices to treat cardiovascular conditions. Their CEO recently described the pathway to approval, including a feasibility study, a pivotal study, and approval to market. In the future, they may look to expand to other indications including epilepsy, depression, sleep, and movement disorders.
Neuralink, one of Elon Musk’s companies, is also planning for future clinical trials for their devices and has established a patient registry. However, they do not currently have any clinical trials available for enrollment.
Pivotal trials
Pivotal trials are studies to establish definitive evidence of effectiveness. In September 2022, ONWARD Medical announced that their pivotal clinical trial evaluating spinal cord stimulation technology to restore function in people with movement disabilities had achieved its primary endpoint. The results prepare them for regulatory submission and commercial launch. The prospective, single-arm study evaluated the safety and effectiveness of a non-invasive device to treat upper extremity functional deficits in people with chronic paralysis of all four limbs. The study enrolled 65 people at 14 medical centers in the U.S., Europe, and Canada. A series of assessments were performed at baseline and monthly thereafter to detect changes in sensory and motor function. An independent data safety monitoring board adjudicated the safe conduct of the study.
Long-term safety studies
Long-term safety studies are often longer studies involving more patients in order to track both the common and the rare side effects. Long-term safety data is needed as neurotech devices are increasingly used in younger patients for longer time periods. Recent results from the BrainGate study, the largest and longest-running clinical trial of an implanted BCI, indicate that the safety of the implanted brain sensors in the study is similar to other chronically implanted neurologic devices, such as deep brain stimulators. The BrainGate clinical trial is run by a consortium working to develop BCIs for people affected by paralysis. The report examined data from 14 adults with spinal cord injuries, brainstem stroke, or ALS who were enrolled in the trial from 2004 to 2021.
Label expansion studies
Label expansion trials are often conducted for devices that have already been approved for a specific condition or patient population with the intent of identifying additional conditions or populations that may benefit. This type of trial can also lead to more revenue for the sponsor. Medtronic conducted a clinical trial in 251 patients that led the FDA to approve their deep brain stimulation therapy for people with earlier disease. In response, a commentary raised questions about safety risks and healthcare costs.
Challenges & Opportunities
In the rapidly evolving field of neurotech clinical trials, there are a number of themes that will be of interest to both the casual observer and the seasoned practitioner. These themes span across emerging and established companies as well as public and non-profit organizations.
Emerging companies
Research translation: Much advanced science is being conducted in animals, but conducting scientific research in humans is harder, for regulatory reasons and because they are more complex. Even when breakthroughs are made in humans, they are difficult to translate into clinical practice. Business incubators exist because it can be hard to get neurotechnology out of the lab and into clinical practice. Promising ideas must cross several “valleys of death”, including lengthy payback periods for investors, challenging technology, and the need for multidisciplinary expertise to get devices to market.
Streamlined trials: Much of the cost and time of developing neurotech devices results from the clinical trial process, which can cost vendors from $30,000 to $50,000 per patient. At the Neurotech Leaders Forum in 2014, a speaker noted that it took upwards of $100 million and 10 years to get a new implantable neuromodulation company off the ground. There is more that neurotech vendors can do to streamline clinical trials, including selecting the most likely trial participants to meet clinical endpoints.
Startup discipline: For neurotech companies, a clinical trial strategy may depend on the company’s overall strategy, whether that may be acquisition, an initial public offering (IPO), or building a sustainable business and product line. Start-up companies may be tempted to try to do too much, but trying to develop multiple products simultaneously may lead to failure or bankruptcy.
Direct-to-consumer market: Some low-risk neurotech devices seek to address general symptoms rather than treating a specific disorder. If they do not claim to treat a medical illness, these devices remain outside of the FDA’s purview. The FDA classifies these products as promoting a healthy lifestyle unrelated to the diagnosis or treatment of a disease or condition. This option may accelerate the development of wellness-focused devices but may be a risk to the neurotech industry. Direct-to-consumer devices such as apps to treat mental health conditions can be developed at substantially lower cost and do not require regulatory review of clinical trials. Numerous other devices are also being developed for non-medical, consumer-oriented computing applications. These could erode the public’s confidence in the utility of neurotechnology to treat illness.
Established companies
Partnerships with pharma: Drugs alone will probably not be effective treatments for some nervous system disorders. Neurology drugs have among the lowest success rates of major drug classes due to limited knowledge about how diseases disturb the nervous system, the mechanisms of action of neurology drugs, how to objectively diagnose conditions besides symptoms or patient perception, how to unambiguously measure drug effects and clinical outcomes, and how to develop drugs that treat the underlying causes of disease. The well-resourced pharmaceutical industry may increasingly seek alternatives to drugs, including neurotechnologies.
Under-reporting of results: It has been widely reported that many clinical trials listed in ClinicalTrials.gov never publish their results in that database or in peer-reviewed journals. In addition, there is a known bias towards publishing positive results but not publishing negative, incomplete or inconclusive results. In an emerging field like neurotechnology where learning is critical, publication of trial results should be seen as a moral responsibility to patients and a financial responsibility to funders. Researchers have also proposed novel study designs to gain knowledge from subjects who do respond to treatment in otherwise “failed” trials to help maximize outcomes and inform the design of future studies.
Telehealth: Clinical trials are often conducted at academic centers, but the ability to gather clinical data remotely through websites and smartphones is enabling investigators to capture data from geographically and socioeconomically diverse sources, and patients are spared the inconvenience and potential safety risks of traveling great distances over long time periods. However, virtual clinical trials have limitations. Some procedures like sophisticated imaging are not available remotely, though participants may have the option to visit a local clinic. Also, some mobile devices may be too complicated for some participants, particularly among older patients or those with progressive disabilities.
Digitization: Clinical trial protocol changes can lead to manual data entry, slowing down trials and increasing costs. Disparate data systems can also create inefficiencies and risk of non-compliance. Clinical trial sponsors are now shifting away from paper-based processes. With better data systems, sponsors can gather feedback from sites and spend less time coordinating surveys. They can distribute safety letters faster to notify sites and regulators in the case of adverse events and get real-time patient updates. For sites, streamlined collaboration frees up time for delivering care to patients. By replacing manual and paper-based processes with digital methods, companies can drive higher quality, lower cost trials and higher patient satisfaction.
Reimbursement: Manufacturers generally seek insurance coverage for their products that is predominantly governed by the Centers for Medicare & Medicaid Services (CMS) in the U.S. CMS determines reimbursement based on data obtained through clinical trials. While the FDA stresses the safety and efficacy of a device, FDA approval does not guarantee patient access to a neurological device. Future clinical trials may increasingly rely on quality of life outcomes and comparative effectiveness studies compared to other treatment options to increase the likelihood of reimbursement.
Public and non-profit funding
Government support: The NIH Blueprint MedTech program is an incubator that seeks to accelerate the development of medical devices, especially from early-stage development to first-in-human clinical trials. The program provides funds and services, including planning resources and expert advice. The program provides support to develop technologies to the point where additional investments are warranted from industry partners, investors, and government. Similarly, the FDA’s Critical Path Initiative is also intended to approve new tools for medical device development for use in clinical trials, and the BRAIN initiative and DARPA also invest in neurotechnology research. Government support of clinical trials could eventually translate to savings for taxpayers.
Philanthropy: A few foundations focused on a specific indication have successfully advanced technologies into clinical trials, but much of the neurotech field struggles to access funding at pivotal points in translating devices to human studies. The result is a bottleneck of first-in-human studies. Philanthropic focus on this barrier could have a positive impact on device development. Early phase human trials focus on assessing safety and initial signals of efficacy, and they inform further device refinement. Many studies at this stage require lower financial support to cover study planning, subject recruitment, and experimentation.
Conclusion
Clinical trials are a required and important step for obtaining regulatory approval of many neurotechnologies on the path towards commercialization. The FDA has increasingly clear guidelines and pathways to support clinical trials of neurotechnologies. In addition, there are an increasing number of successful examples of both early stage feasibility studies and later stage pivotal trials. As the field matures, there will be new opportunities to accelerate and improve the process of studying neurotech devices.
The path will not be easy. Patient and physician acceptance, device miniaturization, safety challenges, the complexity of the brain, data capture and analysis, a shifting market landscape, and other issues must be overcome. Nonetheless, several once-rare, now-routine procedures suggest that invasiveness alone need not stop brain implants from catching on. More than 150,000 people have had electrodes implanted for deep brain stimulation to control Parkinson’s disease. Over 300,000 people have had cochlear implants fitted to improve hearing.
Well-designed clinical trials will likely lead to many more such successes.
Written by Marco Sorani, edited by Lars Olsen and Emily Dinh, with artwork by Chelsea Lord.
Marco Sorani works in biopharma and has a PhD in Bioinformatics. He sustained a spinal cord injury in 1994 and advocates for innovative research approaches.
Lars Olsen is a regulatory medical writer. He works in the pharmaceutical industry writing submission-level documents, and has additional experience with medical devices and pharmacovigilance.
Emily Dinh is a data specialist who works in the medical device industry and is part of a computational cognitive neuroscience lab. She is currently obtaining her MS in Artificial Intelligence.
Chelsea Lord works in clinical operations and is currently working for a company that is a leader in brain-computer interfaces. She studied neuroscience and is interested in the AI and Machine-Learning side of neurotechnology.
