In the research community, many investigators hear the word “FDA” and cringe.

I like to compare FDA-related studies with checking my bank account at the end of the month. Most of us prefer not to look, and if we can get away with it, we’d rather just close our eyes and hope for the best; so long as the debit card is till working, we want to assume whatever we did, it must be fine.

If you’ve ever tried that approach, you may have quickly learned, as I did in my college years, that the long term consequences of that system can be quite painful.

Fortunately, the truth is that as long as we understand it (what we are required to do, what we might not have to do, and how to do it) it’s actually not that bad. That’s been my approach since those dreaded college days, and so I’ve taken the liberty to break down what I know about the FDA’s role in human subject research (take it with a grain of salt).

Sample Scenario 1 – Is it FDA-Regulated?
Dr. Awesome is conducting a study that will test if an investigational radiation-emitting combination of devices can read heart rate better than the currently marketed product. The study is not intended to treat or mitigate any disease or condition. There are no medically-related aspects of the study. The PI simply wants to see if he can create a sensor that works equal or better than a commercially available device that can read physiological vital signs from a distance on moving objects.
Answer is at the end.

Sample Scenario 2 – Is it FDA-Regulated?
Dr. Simple wants to use banked cadaver organs to test an investigational FDA-regulated device. All prior investigations (including animal studies and ex vivo studies such as use of cadaver human tissue) will be included in an IDE application to the FDA.

OHRP defines human subjects as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information“. FDA defines human subject as “an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient.”

While the use of cadaver organs do not meet the federal definition of “human subject” can this study be given a non-human subject determination? And if so, does it still qualify as an FDA-regulated study?

Hint: The FDA regs do not have categories of research that qualify for exempt status like those listed by DHHS. The FDA does not exempt any research under its jurisdiction from IRB review except in emergency circumstances and taste and food quality studies.
Answer is at the end.

Sample Scenario 3 – Is it FDA-Regulated?
Dr. Fabuloso wants to use de-identified blood from a commercial blood bank to test the toxicity of an investigational drug. Going off the definition of human subject, the samples do not appear to be human subject as they are de-identified and the PI cannot identify the people who donated the blood. Since it isn’t identifiable, can it be exempt? Can it be non-human subject? Is it then FDA-regulated?

What makes something FDA-regulated?
Rather than ask if a study is FDA-regulated or not, the question should be, “am I using any type of drug or device in, on, or for humans, and if so, does that need to be reported to the IRB and/or FDA?

After answering that, we can then ask if it is an investigational medical device or a commercially available (i.e., “legally marketed”) device [in the U.S.].

**Note: By being a legally marketed medical device in the U.S., that assumes it is FDA-regulated because it cannot be commercialized in the U.S. unless it has gone through the FDA.

What does this mean?
If you’re using a LASIK machine, yes, you are using an FDA-regulated device. If you are  using an MRI scanner, even if the scanner is legally marketed and commercially available, is it FDA-regulated? Yes! According to the FDA, it is still considered “FDA-regulated”.

Do you need to report the use of these legally marketed devices in your study to the FDA? If it is significant risk and/or requires an IDE, yes! If it has been determined to be a non-significant risk device (NSR), then in most cases, no.

While NSR devices might not require reporting to the FDA, that doesn’t mean the study doesn’t involve an “FDA-regulated device”. Should you add the device to your IRB application? Yes. You should also note if it is being used as Standard of Care (SoC) or for research purposes.

Who Can Determine if the Device is Not Significant Risk?
The Sponsor can determine this, but the IRB must confirm the determination.

Modified Commercial Devices
If the device is used in combination with other devices, or used differently from label, or has any investigational aspect to it (in many cases, the software in an MRI, if used to modify labeled settings, could be considered investigational), and should be included in your IRB application. This may or may not require reporting to the FDA.

In order to use an investigational device in, on, or for humans, it has to either go through the FDA or, if the IRB can make an NSR determination, it can go through the IRB, but the IRB serves as the surrogate for the FDA.

What About Commercial Drugs?
Similar to devices, commercial drugs and investigational drugs both need to be added to your IRB application. Yes, this includes off the shelf vitamins and supplements if used for research.

Page. 12 of the “FDA-regulated Medical Device Studies” explains the IRB’s responsibility to make NSR determinations, and here talks about what qualifies as a Medical Device. There is even a helpful database found here, when we aren’t sure. However, sometimes devices that are not medical (such as any radiation-emitting device and/or electronic products, have additional requirements) and are thus also FDA-regulated.

Apps, Software, and Accessories
It is also important to know that some apps, software, and accessories can also be considered a FDA-regulated and/or a medical device if it meets certain criteria (see here, here, and here).

Scenario 1 – Is it FDA-Regulated?
For electronic products the distinction between med & nonmedical is irrelevant.  However, if a product is being used on humans for research, that would be regulated either by an IRB if the intended use is determined to be non-significant risk (NSR), or it requires FDA review and an approval of the Investigational Device Exemption (IDE) to go forward with the study.

Scenario 2 – Is it FDA-Regulated?
This largely depends on the sponsor, and if they have an IND/IDE already filed with the FDA.
Even if the investigator is reaching out to the IRB for guidance, the sponsor should be consulted in regards to if the study requires FDA oversight (e.g., filing an IDE, IND, 510(k), etc.). That said, sponsors and/or investigators are required to comply with applicable IRB review and regulations with regard to their “clinical study”*, such as IRB approval, unless the study fits under criteria for not needing IRB review (see your IRB for details).

*Important note: a “clinical study” is a research study involving human subjects to evaluate the safety and effectiveness of those interventions (such as device, drug, etc.) on health-related biomedical or behavioral outcomes for certain diseases or specific populations. It aims to ensure the scientific validity, reliability, and reproducibility of the results.

That said, animal and non-human research studies are not considered a clinical study; and thus the IRB and investigational device exemptions (IDE) or investigational drug (IND) regulations do not apply to those types of studies (but may fall under separate or different rules and regulations such as specific sponsor requirements, IACUC review, SCRO review, etc.

The regs state this: Except as provided in 56.104 and 56.105, any clinical investigation which must meet the requirements for prior submission to the FDA or considered in support of an application for a research or marketing permit must have been reviewed and approved by, and remained subject to continuing review by, an IRB meeting the requirements of this part. The key to answering this question is what defines a clinical investigation and what defines “human subject”. In this case, while the study is an investigation that will be used in support of an application for a marketing permit, it is not using human subjects, and thus does not require IRB review, however an NHS (non-human subject) determination is recommended to confirm analysis is not including genetic research.

Here are two useful FDA guidance documents:
IRB Review with IDEs
FDA Regulatory Information

Scenario 2 – Is it FDA-Regulated?
While the device itself is FDA-regulated, that doesn’t mean there is a requirement for IRB review. Current Rule states that with or without identifiers, if it is prospectively collected, it would need IRB review. If the study data will be used to be submitted to the FDA as part of a drug trial it would also need IRB review. However, this again, goes back to the need to consult the sponsor if there is an IDE/IND filed with the FDA, and if there isn’t one, then the sponsor needs to consult with the FDA (who in turn, will need to communicate requirements to the investigators).

Here are two useful FDA guidance documents:
FAQs on IDEs
The IDE Approval Process

In summary, the answer is always grey… Does this leave you feeling more confused than ever? Welcome to the world of research oversight.