Navigating the FDA regulatory landscape

Abstract

Recent research and technological developments have led to an expanding number of novel and rapidly acting therapeutics being developed across a variety of neuropsychiatric disorders. Novel medical devices range from implantable and non-invasive brain stimulating and recording technologies to digital therapeutics. This perspective provides an overview of FDA regulatory oversight for medical devices, including a discussion of regulatory pathways and the review of neuromodulation devices for psychiatric disorders. We highlight the importance of early engagement with FDA and special programs that may be useful to device developers participating in interactions with the FDA that are solution focused. We explore current novel and rapid treatments for psychiatric disorders and those on the horizon. Lastly, we provide considerations for developers in navigating the regulatory landscape for neuromodulation devices intended for psychiatric disorders, including approaches to incorporating patient perspectives.

Introduction

The 21^st century has seen the development of an expanding number of novel and rapidly acting therapeutics designed to diagnose and treat neuropsychiatric disorders. These include a range of medical devices, from implantable and non-invasive brain stimulating and recording technologies to digital therapeutics that can be delivered via smartphone applications. As highlighted in this perspective, there is a shared responsibility between medical device developers and regulators to work together to ensure the timely translation of novel therapies from research breakthrough to clinical application.

Overview of FDA regulatory oversight for medical devices

Medical devices are subject to the regulatory controls in the Federal Food, Drug, and Cosmetic Act (FD&C Act). The Center for Devices and Radiological Health (CDRH) has responsibility for the review and authorization of medical devices under its purview [1] before they can be legally marketed in the US, enforcing compliance with the laws and regulations set forth for medical devices, including the quality system regulations, as well as monitoring of adverse event reports and other problems with medical devices (e.g., recalls) once the device is legally marketed [2]. CDRH, within the Food and Drug Administration (FDA), is responsible for assuring that patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products [3]. The Office of Neurological and Physical Medicine Devices (or Office of Health Technology 5 (OHT5)) within CDRH has the primary responsibility for oversight of neurological and physical medicine devices ranging from types of medical devices such as neuromodulation, neurostimulation, digital health, and brain computer interface devices, to neurosurgical, neurointerventional, and neurodiagnostic devices.

FDA utilizes a risk-based classification scheme to determine the level of regulatory control needed to provide a reasonable assurance of the safety and effectiveness of a medical device. FDA classifies devices as Class I, II, or III with regulatory control increasing from Class I to Class III [4]. The device classification requirements are found in the Code of Federal Regulations (CFR) Title 21 for a general device type. Classification of neurological devices are outlined in 21 CFR Part 882, which device developers can reference to understand the classification of a specific neurological device type [5]. There are no neuromodulation devices for psychiatric disorders that are class I, but an example of a neurological class I device is a ventricular cannula (ventricular needle) used to puncture the ventricles of the brain for aspiration or for injection. Repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depressive disorder in patients who have failed at least one antidepressant medication and are currently not on any antidepressant therapy is an example of a class II neurostimulation device. An example of a class III neurostimulation device is an implanted vagus nerve stimulator for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.

CDRH uses a Total Product Life Cycle (TPLC) model to implement its regulatory oversight of medical devices, linking development, regulatory review and authorization to post-market surveillance and continued compliance with the laws and regulations implemented by FDA [6]. For example, data from medical device reports (MDRs) may help inform regulatory review before a device is legally marketed in the US or potential modifications to the labeling of a legally marketed device.

Regulatory oversight and review of neuromodulation devices

There are several regulatory pathways available to bring medical devices to the market. The specific pathway is determined by the degree of oversight needed to provide a reasonable assurance of safety and effectiveness. For example, most Class I devices (low to moderate risk) are subject to general controls [7] and most are exempt from a marketing submission to FDA; generally Class II devices (moderate to high risk) require Premarket Notification, also known as a 510(k) submission; and Class III devices (high risk) require Premarket Approval (PMA) [8]. The 510(k) review process determines whether a new device is substantially equivalent (or as safe and as effective) to a legally marketed device that is not subject to PMA, known as a predicate device. A determination of substantial equivalence of the new device to its predicate device is based on an evaluation of intended use and technological characteristics of the new device compared to a predicate device. For class II devices subject to the 510(k) review process, sponsors must receive FDA clearance of their 510(k) submission prior to marketing the device [9]. The PMA is a process to evaluate the safety and effectiveness of Class III medical devices and typically relies on clinical and non-clinical performance data to demonstrate a reasonable assurance of the safety and effectiveness for the device. For class III devices subject to the PMA review process, sponsors must receive FDA approval of their PMA application prior to marketing the device [10].

The De Novo classification request is an additional regulatory pathway for novel medical device types not available on the market before the passage of the Medical Device Amendments of 1976, and hence, for which there are no comparable device types (i.e., predicate device) legally on the market. If FDA finds that the data and information provided demonstrate that general controls or general and special controls are adequate to provide reasonable assurance of safety and effectiveness, and the probable benefits of the device outweigh the probable risks, FDA will grant the De Novo request and establish a new classification regulation for the new device type.

Another more specialized regulatory pathway is that of the Humanitarian Device Exemption (HDE), which is for devices intended to treat or diagnose rare diseases or conditions affecting fewer than 8000 patients per year in the US [11]. A deep brain stimulation device for obsessive-compulsive disorder has been approved under this pathway [12].

The Office of Neurological and Physical Medicine Devices (OHT5) provides dedicated and focused review of clinical trials and marketing submissions for neuro-technologies. The Neuromodulation Psychiatry Devices Team within OHT5 reviews external and implanted neurostimulation and neuromodulation devices as well as digital therapeutic devices that are intended to treat a variety of psychiatric conditions, ranging from major depression and obsessive-compulsive disorder to attention-deficit/hyperactivity disorder and insomnia. During the review of any given submission, OHT5 assembles a review team depending upon the expertise required. This team works interactively with sponsors during the review of the submission, and OHT5 makes a final decision on the marketing submission.

During device development it is often necessary for sponsors to conduct clinical studies as part of the performance testing to support the safety and effectiveness of the device. For clinical studies that are determined to be of significant risk to patients, sponsors must obtain FDA approval of an Investigational Device Exemption (IDE) and Institutional Review Board (IRB) approval prior to initiation of a clinical study in the US [13]. The sponsor is responsible for making the initial determination of whether a study will pose significant risk to patients and then presenting their determination to the IRB [14]. Sponsors may also obtain a determination by FDA through a specific type of Q-Submission referred to as a study risk determination [15].

Early engagement with FDA

The Q-Submission (or Q-Sub) Program allows sponsors to engage with the Agency early during device development, before a marketing submission, and during a marketing submission review. Sponsors are encouraged to interact with FDA staff early and often to obtain feedback before submitting a marketing application or IDE. Through the Q-Submission program, sponsors may obtain feedback from FDA regarding specific questions on clinical study design, non-clinical testing, and animal testing, including the type of testing and methodology necessary, to support a future marketing submission or an IDE. Sponsors may also choose to interact with FDA staff via a type of Q-Submission known as an “Informational Meeting” to provide general information and an overview of new or novel device types, without expectation of FDA feedback.

Special programs

Novel and rapid therapies may qualify for, and benefit from, several unique programs FDA offers to encourage medical device development. One such program, Breakthrough Devices, is a voluntary program that provides manufacturers options for interactions with FDA for certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. Such interactions can include sprint discussions, which are discussions with FDA on a single topic (e.g., strategy for focused non-clinical testing, clinical protocol design) with specific goals (e.g., determining primary and secondary endpoints for a pivotal study) to achieve resolution within a set time period. Other interactions can include a request for discussion on a data development plan and a request for clinical protocol agreement [16]. When considering whether a device indicated for a psychiatric disorder provides for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human diseases or conditions, it is important to consider the target patient population and what information is available to demonstrate the effect the device is intended to have on the target population beyond that of any concurrent treatment or medications.

FDA recently launched the Total Product Life Cycle Advisory Program (TAP). TAP supports the CDRH vision to help ensure that U.S. patients have access to high-quality, safe, effective, and innovative medical devices first in the world for years to come. TAP is designed to do this by promoting early, frequent, and strategic communications between the FDA and medical device sponsors [17].

The Safer Technologies Program (STeP) is another voluntary program to help reduce the time it takes to develop and obtain marketing authorization for eligible devices. STeP is specifically for certain medical devices and device-led combination products that are reasonably expected to significantly improve the safety of currently available treatments or diagnostics that target an underlying disease or condition associated with morbidities and mortalities less serious than those eligible for the Breakthrough Devices Program. Similar to the Breakthrough Devices program, options for interaction include sprint discussions and requests for discussion on a data development plan. STeP interactions may also include obtaining feedback through a traditional Q-Submission or agreement for regular status updates to discuss a sponsor’s general progress on the project [18].

These programs may be useful to device developers by providing frequent interactions with the FDA that are solution focused and guidance from other medical device stakeholders within the total product life cycle of a medical device.

Novel and rapid treatments for psychiatric disorders

Novel device treatments for psychiatric disorders have explored both the refinement and precision delivery of existing neurostimulation technologies as well as the development of new device technologies - from novel brain stimulation devices to digital behavioral therapies. The clinical research literature highlights growing interest in both non-invasive and invasive neurostimulation and neuromodulation technologies such as rapidly delivered and targeted rTMS, transcranial direct current stimulation (tDCS), deep brain stimulation (DBS) using novel targeted stimulation and adaptive stimulation, magnetic seizure therapy, and low-intensity ultrasound for neuromodulation. Many of these new technologies hold the potential for rapid delivery of therapy, through shorter stimulation sessions, more precise targeting, or improved access to care.

Examples of new technologies with potential for rapid delivery of therapy include therapies that have built upon FDA-cleared repetitive transcranial magnetic stimulation (TMS) therapies. Specifically, intermittent theta burst (iTBS) TMS and TMS with accelerated treatment protocols have decreased the duration of each session as well as the total duration of treatment. Both iTBS TMS and TMS with an accelerated treatment protocol have recently been cleared for the treatment of major depressive disorder (MDD) in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode [19–24]. In addition, rTMS as an adjunct for the treatment of adult patients suffering from obsessive compulsive disorder has also recently been cleared [25–29]. Other neurostimulation and neuromodulation devices have more recently come to market to aid in treating patients with psychiatric disorders, including the following device types: percutaneous nerve stimulator for substance use disorders [30–32], transcutaneous electrical nerve stimulator for attention deficit hyperactivity disorder [33], digital therapy device for Attention Deficit Hyperactivity Disorder [34], and digital therapy device to reduce sleep disturbance for psychiatric conditions [35].

There is extensive ongoing research of novel neuromodulation approaches. The U.S National Library of Medicine ClinicalTrials.gov website serves as a resource for identifying devices that are currently under investigation prior to FDA authorization. For example, the ClinicalTrials.gov website lists several investigations on the use of accelerated TMS for suicidal ideation [36]. Magnetic seizure therapy for depression is another novel neurostimulation approach for which several studies are listed [37]. ClinicalTrials.gov also lists ongoing investigation on the exploration of low-intensity focused ultrasound for a variety of conditions [38]. Invasive therapies using novel targeted deep brain stimulation (DBS) [39] and closed-loop stimulation [40] approaches are also building on existing platforms.

Digital therapeutics is another area of novel therapy development that holds the potential for increased, and potentially rapid, access for patients. Digital therapeutics include novel therapies such as computerized forms of common behavioral therapies and can be delivered through devices such as a smartphone application or virtual reality headset.

Three device classification regulations for digital therapies in psychiatry have been established in recent years, including: computerized behavioral therapy device for psychiatric disorders (21 CFR 882.5801) [41], digital therapy device for attention deficit hyperactivity disorder (21 CFR 882.5803) [34], and digital therapy device to reduce sleep disturbance for psychiatric conditions (21 CFR 882.5705) [42]. CDRH is advancing and realizing the potential of digital health, including the use of digital health devices for the treatment or diagnoses of psychiatric disorders. CDRH established the Digital Health Center of Excellence to align and coordinate work across FDA to advance healthcare by fostering responsible and high-quality digital health innovation [43].

As mentioned above, computerized behavioral therapy devices for psychiatric disorders, a type of digital therapeutic, provide a type of behavioral therapy for a psychiatric condition. These devices are prescription devices that are intended to provide a computerized version of condition-specific behavioral therapy as an adjunct to clinician supervised outpatient treatment for patients with psychiatric conditions. The computerized behavioral therapy device is intended to provide patients access to therapy tools used during treatment sessions to improve recognized treatment outcomes. Beyond computerized versions of a condition-specific behavioral therapy, researchers continue to explore other digital platforms and technologies such as gaming, virtual reality, artificial intelligence, and machine learning, to advance treatment and diagnosis of psychiatric disorders.

Navigating the regulatory landscape for neuromodulation devices

With the development of novel and rapidly acting devices for use in the psychiatric space comes the need for an understanding of how to navigate the regulatory process. When thinking about development of a neuromodulation device for psychiatric disorders, it is important that sponsors consider the intended use and indication for use of the device, the intended patient population, the device’s technological characteristics, and the data needed to support a marketing submission. These factors are important in terms of establishing a reasonable assurance of safety and effectiveness of the device in the case of a PMA approval or De Novo authorization, or demonstrating substantial equivalence of the intended use and technological characteristics of a new device compared to a legally marketed predicate device in the case of a 510k. Also, keep in mind that the principles of safety and effectiveness are factors that are considered in the determination of substantial equivalence [44].

For neuromodulation devices, it is also important to consider the type of data that will demonstrate the level and duration of clinical benefit being provided to the patient compared to the risks associated with the device, including both device risks and risks associated with the target patient population. For example, while certain neurostimulation devices may have risks such as skin irritation, headache, seizure, hemorrhage, lead or implant migration, worsening of symptoms and suicidality are additional risks to consider. It is essential for sponsors to consider performance data (clinical and non-clinical) that will demonstrate the device effect, and to consider the development of a well-designed control arm given the high placebo effect in many psychiatric disorders as well as clinically significant results for the target patient population. FDA has developed three guidance documents to provide greater clarity for FDA reviewers and industry regarding the principal factors FDA considers when making benefit-risk determinations during the premarket review process for certain medical devices [45], for evaluating the benefit-risk profile of a new device in comparison to the predicate device [46], and when assessing the benefits and risks of IDE applications for human clinical studies [47].

It is essential that sponsors consider how to design their study to support the indication for use and target patient population; and establishing clinically meaningful study endpoints is an important consideration to support study success. Including a formal hypothesis and pre-established study success criteria in the clinical study protocol and statistical analysis plan are additional key elements to help support study implementation and success. What constitutes a clinically significant result both within a study arm and between the active arm and control arm is also an important consideration, which, when pre-established in the study protocol, helps to reduce bias and uncertainty in the study results. Conducting well controlled studies that include appropriate blinding, sham-control, and randomization is another critical consideration.

Patient perspectives

Novel approaches to assessing patient experience [48] can be incorporated into, and benefit, the development of novel and rapidly acting therapeutics. Patient experiences can be tracked by clinical outcome assessments (COAs) of which there are four forms: Patient-reported outcomes (PROs), Clinician-reported outcomes (ClinROs), Observer-reported outcomes (ObsROs), and Performance outcomes (PerfOs) [49]. Each of these COAs focuses on the patient’s health status from different perspectives. When an investigator is able to incorporate high-quality COA data in their submission, this allows for generation of valuable evidence which can be used in the review process to understand the balance of risks and benefits of device use. Additionally, patient preference information (PPI) can be obtained by way of well-designed and conducted studies that are able to provide estimates of how much different outcomes, endpoints or other attributes are valued by patients, and the tradeoffs that patients state or demonstrate they are willing to make among them [50]. One example is the Parkinson’s patients’ tolerance for risk and willingness to wait for benefits of novel neurostimulation devices study [51]. This study used the threshold technique to quantify patients’ risk thresholds for new or worsening adverse outcomes in exchange for improvements in various symptoms. In this way the investigators were able to elicit valuable insights into patients’ willingness to wait to receive treatment benefit. This and other types of PPI can be used in all stages of device creation to incorporate important patient perspectives, from initial design to formation of the clinical study to post-market impact assessments.

Summary

The field of neurostimulation and neuromodulation is bustling with the development of novel technologies that have the potential for more rapid therapies for a variety of psychiatric disorders. CDRH plays a key role in facilitating the development of novel neurostimulation and neuromodulation technologies and enabling U.S. patients and caregivers timely access to such technologies. Understanding FDA’s role and the various regulatory pathways and initiating early interactions with FDA are important aspects of successful medical device development. Early interactions introduce novel technologies to the FDA early in development and help manufacturers understand expectations in terms of non-clinical and clinical evidence development to demonstrate the safety and effectiveness of a device and support bringing the device to the marketplace.

Ultimately, evaluation of the safety and effectiveness for a novel technology will need to include understanding the clinical benefit for the target patient population and how those benefits outweigh the risks based on clinically meaningful and statistically significant results, while folding in patient perspectives when applicable. CDRH takes a least burdensome approach by tailoring our scientific and regulatory review to the specific type of medical device, to ensure that CDRH is meeting the public’s expectations as a public health agency and its mission of protecting and promoting the public health.

Author contributions

PDS wrote and edited the manuscript, AB wrote the Patient Perspectives section and contributed to editing the manuscript, DPM wrote the introduction, contributed to the Special Programs section and the Novel and Rapid treatments for Psychiatric disorders section, and edited the manuscript.

Competing interests

The authors declare no competing interests.