Abstract
Researchers and companies developing new concepts in neuromodulation will, at some point, find themselves navigating the US Food and Drug Administration (FDA) regulatory programs, whether during the conduct of a clinical trial or at the time market approval is sought. While established companies may have experience with the broad scope of regulatory requirements, most early stage researchers and small companies do not, and therefore do not benefit from learned strategies of interaction with the agency.
Keywords
Benefit, Food and Drug Administration, Least burdensome, Regulations, Risk
Outline
Brief History of Medical Device Regulation 1675
Time and Cost of Device Development 1676
Investigational Device Exemption (IDE) 1676
Determining Whether an Investigational Device Exemption (IDE) Is Needed 1677
Investigational Device Exemption (IDE)-Exempt Studies 1677
Nonsignificant Risk Studies 1677
Early Feasibility Investigational Device Exemption 1678
The Case for an Investigational Device Exemption 1678
Device Classification 1679
Market Approval for Neuromodulation Systems 1680
Premarket Application (PMA) 1680
Traditional 510(k) 1680
De Novo 510(k) 1683
Humanitarian Device Exemption (HDE) 1683
Innovation Pathway and Expedited Access Pathway 1684
Postmarket Regulation of Neuromodulation Devices 1684
Conclusions 1684
References 1684
There are considerable resources available that researchers can draw on to self-educate on the basics of regulatory requirements ( ). These sources are useful for identifying the ways in which regulatory oversight applies, detailing the necessary requirements at each stage. However, many researchers and clinicians do not appreciate that there are steps along the regulatory pathway that can be vague or ambiguous, or that some requirements can be negotiated. Because the FDA uses a risk-based approach to medical device regulation, there are different levels of oversight that result in higher or lower regulatory burden, where those higher requirements may cost more in terms of both time and money. Given that the “21st Century Cures Act,” which revamps FDA’s laws, continues to place emphasis on the “least-burdensome” approach to medical device review, it behooves early-stage researchers to provide expert arguments and evidence-based rationales for those products that are intended to address unmet medical needs, for which a “least-burdensome” approach is critical. This chapter introduces the basic elements of FDA’s regulatory oversight, and is directed to early-stage developers of neuromodulation technologies, typically academic researchers, clinical investigators, and small start-up companies.
Brief History of Medical Device Regulation
It’s easy to forget that the FDA has been regulating medical devices only since 1976 with the passage of the Medical Device Regulation Act, a congressional reaction to the 1973 spate of lawsuits over the Dalkon Shield intrauterine device in which over 200,000 women claimed injury following use of the implant ( ). This is a relatively short history of regulatory oversight, in stark contrast to the century-long regulation the agency has provided over biologics (1902), food (1906), and drugs (1906). The laws crafted in the 1970s for oversight of medical devices were intended to provide a modern regulatory framework that acknowledged the significant differences between engineered medical devices, as compared to drugs and biologics, while allowing for a similar risk-benefit approach. Subsequent amendments to the law, including the Food and Drug Modernization Act (1997), the Medical Device User Fee and Modernization Act (2002, with its reauthorizations in 2007 and 2012), and the FDA Innovation and Safety Act (2012), strengthened the FDA’s postmarket regulatory authorities, introduced user fees while specifying statutory review times, and promoted innovation. The introduction of user fees has done the most to shape the inner workings of the FDA, bringing tighter control over review times and resulting in a more predictable experience for industry. The evolving history of FDA’s regulatory framework for medical devices incorporates some of the most sophisticated thinking about product regulation than any other regulatory body, with legal authorities extending from before a company begins studying a device in humans through market approval and including postmarket requirements for adverse event (AE) reporting, product recalls, advertising, and promotion.
Time and Cost of Device Development
With the introduction of medical device laws, the previously unfettered pursuit of technological solutions to medical problems in the 1960s and 1970s gave way to increasing regulatory oversight in the 1980s until today. A number of sophisticated neuromodulation technologies used in cardiac electrophysiology were already part of standard care at the time FDA began regulating medical devices, including pacemakers and external defibrillators (1950s). Methods of neural recording were also clinically in use prior to the introduction of FDA regulations: electrocardiography (1930s); electroencephalograpy (1940s); and electromyography (1940s). The first three decades of FDA authority over medical devices saw the introduction of a number of innovative concepts in neuromodulation, including the approval of the first spinal cord stimulator for pain relief (1978), the first bone growth stimulator (1979), the first cochlear implant (1985), and the first neuroprosthetic to restore function (1997).
Investigators and small start-up companies pursuing new medical technologies often found the FDA requirements overwhelming, particularly at the earliest stages of development. Recognizing this, Makower, et al. conducted a survey of over 200 medical device companies to calculate the time and cost associated with bringing medical technologies to market, including those activities tied directly to FDA’s requirements. The resulting 2010 report, “FDA Impact on Medical Technology Innovation” ( ) showed that the cost to bring a Class II (defined in Table 142.3 ) product to market averaged $31 million, including $24 million in FDA-dependent, or FDA-related activities. The cost to bring a Class III (defined in Table 142.3 ) product to market averaged $94 million with $75 million directed toward FDA-related activities. The report further underscored the fallacy of “statutory review times,” pointing out that the total time—from FDA’s receipt of an application to its final approval—often exceeded the statutory time by considerable margins. The statutory review time for a Class II device is 90 days, but the effective total time was found to be 10 months. Likewise, for Class III devices, the agency reported average total interaction times of 9 months, whereas survey respondents reported effective total time of 54 months.
Similar criticisms leveled by congress ( ), and demands for FDA to abandon sections of its laws ( ) resulted in the creation of several internal programs designed to improve transparency, facilitate the early stages of translation, and promote innovation. The 2011 Innovation Initiative saw the start of new efforts, including the Innovation Pathway program, which this author directed ( ) and later evolved into the Expedited Access Pathway ( ); the Early Feasibility Investigational Device Exemption (IDE) Pilot ( ); and critical improvements in the De Novo 510(k) pathway ( ), all of which are discussed in this chapter.
Investigational Device Exemption (IDE)
FDA’s premarket regulatory authority restricts medical device companies from introducing their products into interstate commerce without prior approval from the FDA. This restriction is waived in the case of companies wishing to study an investigational device, and hence the word “exemption” in the term IDE. An approved IDE permits the holder to manufacture, ship, and sell medical devices under controlled conditions, to collect evidence to support either a marketing application or a research objective, and without complying with other requirements necessary for devices in commercial distribution.
The IDE regulations referenced in Title 21 Code of Federal Regulations, Section 812, only specify what companies should submit; the regulations do not provide a framework for review. This is in contrast to the framework for review established for premarket applications (PMAs) (“reasonable assurance of safety and effectiveness”) and 510(k)’s (“substantially equivalent to a predicate”). However, an implicit, but unstated, framework for IDEs has evolved over time to include two main ideas. First, an investigational device must be safe enough to begin use in humans. This concept underscores FDA’s emphasis on safety over effectiveness, although proof-of-principle may need to be established. Basic elements of “safety” include a device’s biocompatibility, sterility, electrical safety, mechanical reliability, software performance, and electromagnetic compatibility. Second, the investigational plan itself must be designed to generate evidence to support a marketing application. In the past, this resulted in IDE disapprovals that were based on study design, hypotheses, or statistical analysis plans, even though the device itself was safe enough to begin use in humans. The FDA modified its approach to IDE decision-making, allowing FDA reviewers to separate their review of safety from their review of the study design. At the same time, the agency developed new internal processes to facilitate the clinical trials enterprise, following criticism that the high regulatory burden in the US was causing companies to abandon US studies in favor of clinical trials in Europe, Asia, and elsewhere. The result is that from 2011 to 2014, the median number of days to full IDE approval decreased from 442 to 101 days ( ).
One way this was achieved was to correct a misperception about the meaning of FDA’s decisions for IDE’s. “Approved” and “Approved with Conditions” both legally permit the start of the clinical trial. However, in the past, many Institutional Review Boards (IRBs) would not honor the conditional approval status, sometimes re-reviewing FDA’s concerns and conducting their own assessment, further delaying the start of the study. FDA corrected this in 2014, making it clear that even conditionally approved studies could begin enrolling patients ( ).
Determining Whether an Investigational Device Exemption (IDE) Is Needed
There are two statutory criteria used to determine whether a study requires an IDE. The first is whether the study meets the definition of “IDE Exempt,” and the second is whether the study meets the definition of “Non-Significant Risk.” In either case, the decision is made, not by submitting a request to the FDA, but rather by presenting a rationale to an investigator’s local IRB. FDA recognizes the IRB as the primary adjudicator of whether an IDE is necessary and prefers not to weigh in on these decisions.
Investigational Device Exemption (IDE)-Exempt Studies
IDE-Exempt studies [21 CFR 812.2(c)] are those that meet one or more of the criteria outlined in Table 142.1 . The table also provides examples of IDE-exempt studies relevant to the neuromodulation community.
| Criteria | Examples |
|---|---|
| A legally marketed device used in accordance with its labeling. |
|
A diagnostic device, if it complies with labeling requirements in 21 CFR 819.19(c), and if the testing:
|
|
| Consumer preference testing of a legally marketed device. |
|
Nonsignificant Risk Studies
A nonsignificant risk study is one involving a medical device that does not meet the definition of significant risk ( ), as outlined in Table 142.2 .
|
The significant risk definition hinges on the interpretation of terms such as “implant,” “serious risk to health,” and “supporting or sustaining human life,” for which there can be considerable variation in interpretation. In situations where there is a question about whether a device is significant risk, investigators wishing to pursue a least-burdensome pathway are encouraged to provide evidence and rationales that the device under study meets the definition of nonsignificant risk. In the next section, some clarification of these terms is provided.
Implant
No regulatory definition exists. FDA uses its biocompatibility guidance ( ) as a rule of thumb, which characterizes devices as being “surface devices” (making contact with skin); “externally communicating devices” (indirect blood path contacting, tissue/bone/dentin contacting, or contacting circulating blood); and “implants” (making contact with tissue/bone, or blood). These are further categorized by the duration of contact, including “limited” (<24 h), “prolonged” (24 h–30 days), and “permanent” (more than 30 days). An “implant” can be assumed to be a device that makes permanent contact with tissue, bone, or blood, and does not externally communicate through the skin. Temporary (<30 days), percutaneous, neural recording electrodes are an example of a device that could qualify as nonsignificant risk on this basis. Skin-contacting, neural recording systems, or oral, vaginal, or rectal neural probes could similarly be classified as not an implant, particularly if used on a limited basis.
Serious Risk to Health
No regulatory definition exists; the FDA often reverts to its definition of “serious adverse events (SAEs),” which includes death, life-threatening events, events that result in an initial hospitalization, or prolongation of an existing hospitalization, disability, or permanent damage, congenital abnormality or birth defect, or any event requiring intervention to prevent permanent damage or disability. A device that “presents a serious risk to health” is one that has the potential to cause a SAE if the device should fail.
Supporting or Sustaining Human Life
Life-supporting or life-sustaining devices are typically considered devices that directly maintain heart, respiratory, or brain functions, such as pacemakers, defibrillators, and ventilators. However, this is often extended to include many other cardiac and peripheral vascular devices, respiratory, and neurological devices.
Both sponsors and investigators of nonsignificant risk studies must comply with an abbreviated set of regulatory requirements as outlined in two FDA documents, “Responsibilities of Sponsors of Nonsignificant Risk Device Studies” and “Responsibilities of Investigators for Nonsignificant Risk Device Studies” ( ). Among the responsibilities are provisions for investigational labeling, obtaining IRB approval, obtaining informed consent, appropriate monitoring of AEs, appropriate record keeping, and the prohibition of marketing and promotional activities.
Early Feasibility Investigational Device Exemption
The Early Feasibility IDE program was introduced as a pilot effort in 2011 as a program within the Innovation Pathway to foster innovation in the medical device sector by providing a new framework for review of early stage clinical trials ( ). The pilot program initially accepted nine applicants and was eventually codified into practice with the publication of a final guidance document in October 2013. The Early Feasibility IDE program established an appropriate framework for review by recognizing that early stage clinical trials of novel medical devices often require iteration in the design of the device to bring it into final form. The program, which mitigates risks to patients by limiting such studies to 10 or fewer subjects, permits ongoing development of the technology during the course of the study, and allows some final device testing to be performed after the trial has commenced.
The Case for an Investigational Device Exemption
In the previous sections, it has been shown that rational arguments can be made in support of IDE-Exempt or nonsignificant risk studies, and in that way the FDA’s oversight over a clinical trial can be minimized. An aggressive, least-burdensome approach is possible, and certainly investigators wishing to avoid all FDA oversight are free to conduct their clinical trials outside the United States. However, avoiding regulatory oversight also means losing an opportunity to benefit from the insight that comes from an expert FDA review. Investigators should remember that the FDA review of an IDE also includes an evaluation of the robustness of the clinical study design itself, and often FDA’s concerns are a preview of its areas of focus for the future marketing application. The best arbiter of whether a trial design will result in the evidence necessary to support a marketing application is the FDA itself, and its review of a study’s primary endpoints, hypothesis, sample size, patient follow-up, and statistical analysis plan are valuable feedback at the earliest stages of a clinical trial.
The single greatest factor that determines the level of regulatory oversight over an IDE is whether the clinical evaluation is being explored for research purposes only, versus a step toward commercialization. Investigators need to be realistic about this delineation: if the goal is to publish results and apply for follow-on funding, then the study is intended for research purposes only, and this may result in lower regulatory expectations.
The obvious counterpoint is that the impact of a scientific or engineering discovery will be greatly reduced if it never becomes widely adopted as a commercial product. Much has been written about the ethical principles involved in the conduct of clinical trials for investigational devices and drugs ( ), and most researchers are familiar with the concepts of the Declaration of Helsinki, which outlines patient protection measures for human research ( ). However, in the field of neuromodulation, a further concern is whether there is a trend toward ongoing experimentation on patient populations who may never benefit from a commercial product. For this reason, commercialization needs to be pursued with intention.
Device Classification
FDA’s regulations permit the use of a risk-based approach to regulating medical devices, allowing different degrees of oversight (called “controls”) to be placed depending on the level of risk the device poses, as noted in Table 142.3 . Controls are codified in to general controls, such as registration, listing, and good manufacturing practices; special controls, such as special labeling requirements, mandatory performance standards and postmarket surveillance; and premarket approval, which requires the conduct of a clinical trial to provide the evidence of safety and effectiveness of the device.
Related posts:
Fundamentals of Burst Stimulation of the Spinal Cord and Brain
Advances in Invasive Brain–Computer Interface Technology and Decoding Methods for Restoring Movement and Future Applications
Neurostimulation for the Treatment of Complex Regional Pain Syndrome
Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus Improves Static Balance in Parkinson’s Disease
Neuroprostheses for Restoring Sensation
Transcranial Alternating Current Stimulation and Transcranial Random Noise Stimulation
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