Medical Devices: “Significant Risk” Versus “Nonsignificant Risk” Determinations

In medical device research, the determination of “significant risk” or “nonsignificant risk” is sometimes confusing, especially for those new to device research. Unique to the device space, this risk determination is not the same as a “no more than minimal risk” determination often made for studies potentially eligible for expedited institutional review board (IRB) review.

Let’s take a closer look at what significant risk (SR) and nonsignificant risk (NSR) determinations mean for medical device clinical trials.

Definitions

Here’s a quick look at the definitions provided in the Food and Drug Administration’s (FDA’s) information sheet on SR and NSR medical device studies. If you’re not familiar with this document and work in this space, I strongly suggest you give it a read for more detailed information on these risk determinations and their implications.

Under 21 CFR 812.3(m), an SR device study involves an investigational device that:

• Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a research subject;
• Is meant to be used to support or sustain human life and presents a potential for serious risk to the health, safety, or welfare of a subject;
• Plays an important role in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject;

OR

• Otherwise presents a potential for serious risk to the health safety or welfare of a subject.

Conversely, an NSR device study is one that does not meet the above definition.

You’ll notice each option in the SR definition mentions “a potential for serious risk to the health, safety, or welfare of a subject.” If the investigational device meets one of these criteria and is deemed SR, the device will require an investigational device exemption (IDE) for the study to commence.

It’s possible a study can be determined SR even when the device under investigation was previously determined NSR. An approved laser may operate at more than one energy level or with various accessories according to the clinical setting and intended application, so the potential use may range from SR while others are NSR. Another example is a scope and/or another device used in a more invasive clinical setting than originally approved, which makes the device higher risk. The determination is based on how the device will be used in a particular study, not on the device alone.

SR/NSR Determinations are not Minimal Risk Determinations

Understandably, the SR/NSR risk determination is often confused with “no more than minimal risk” determinations. A “minimal risk” study means the research involves no greater than minimal risk to study subjects (i.e., the level of risk an average healthy person would expect to encounter during typical daily experiences), and it can be reviewed via expedited review, conducted by a designated IRB member rather than the fully convened IRB. SR/NSR and minimal risk determinations are separate and distinct. Just because a device study has been determined NSR does not mean the study would be considered minimal risk. In fact, it is possible and not uncommon to deem an NSR device study as greater than minimal risk, since its use in a study may represent more risk than described in the minimal risk categories, but clearly not significant in that it represents potential for serious risk to the health, safety, or welfare of a subject (not SR).

The Study is Determined “Significant Risk” — Now What?

The key differences between SR and NSR studies are found in the IDE approval process and in the sponsor’s reporting and record-keeping requirements.

More oversight and reporting are required for SR device studies since they are riskier by definition. The study sponsor must submit an IDE application and receive FDA approval of the study. An IRB may review an SR study while FDA is reviewing the IDE application, but the study cannot begin until the agency approves the IDE. The IDE brings with it additional responsibilities with which researchers must comply; for more information, check out FDA’s Device Advice section on IDE responsibilities (IDE responsibilities are outlined at 21 CFR 812.40 and subsequent parts of Subpart C).

Since NSR device studies are inherently less risky than SR studies, the agency imposes less stringent controls. The IRB serves as the surrogate for the FDA’s review, approval, and continuing review of NSR device studies. Therefore, an NSR study may begin with IRB approval and continue without prior FDA approval.

Making the Determination

The study’s sponsor is responsible for proposing the initial risk determination. The sponsor will submit a proposal based on the regulatory criteria to the IRB for consideration. FDA is also available to help make the determination, and in some cases, it’s possible the FDA has already made the risk determination before the study reaches the IRB. In these cases, the FDA’s determination is final.

If FDA hasn’t already made the risk determination, then it’s up to the IRB to decide whether it concurs with the sponsor’s risk assessment. The IRB may disagree with the sponsor’s assessment. Here are some key items the IRB will consider:

• The basis for the risk determination
• The type of harm resulting from device use
• Any additional procedures a study subject may need to undergo as part of the study (the IRB must assess the potential harm of the procedure as well as of the device itself)

It is possible for the IRB to approve a SR device study with the condition that the study may not commence until the FDA provides an IDE.

Hot Spots

There are investigational devices that in themselves do not pose harm to subjects, but their use may impose significant risk. For example, an investigational diagnostic assay may detect a genetic variant present in tumor cells, making the tumor susceptible to treatment with a targeted chemotherapy. The device itself is never in contact with the study subject, but the sampling required to obtain tumor tissue (biopsy) may be invasive and pose significant risk. Additionally, as an investigational assay that has not been validated by another “gold standard” device, it poses risk related to false positive or false negative results. If results from the assay determine eligibility for study entry or direct the clinical care of the subject (e.g., treatment assignment, dosing), false positive results would impose risks related to the side effects of the drug with little likelihood of response and delay the subject from obtaining effective treatment. Conversely, false negative results would prohibit entry into a study which holds out the prospect of benefit.

In a similar vein, an investigational continuous blood glucose monitor may pose minimal physical risk from the device itself in the form of irritation or infection from the sampling pod. But the consequences of false readings from the device are significant and life-threatening if the subject receives false readings of their blood glucose levels.

Understanding the nuances of these determinations is critical for both the sponsor and IRB alike. The SR/NSR determinations are unique as they represent the delegation of duties from the FDA to the IRB to act as its surrogate in determining the regulatory status and pathway of an investigational device. If you’re ever unsure about a determination or want more information, your IRB is a great source to reach out to for any questions you may have.

Note: This article was originally published October 31, 2017, and has been updated to include new and clarifying information.

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