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Aug2022

On May 3, 2022, PRIM&R hosted a webinar, Un-Common Rules: Navigating FDA-Regulated Research and the IRB. During the webinar, Belinda Smith, MS, RD, CCRC, explored the differences between FDA and Common Rule regulations, how the differences are tied to the unique mission of the FDA, and guidance on when and how to apply FDA regulations to IRB review.

The range and volume of questions submitted after the webinar illustrate a need for guidance on applying the FDA regulatory framework to IRB review, particularly in unique cases. After reflecting on the session, attendee feedback and questions, I am pleased to provide suggestions for navigating the complex framework and answers addressing themes about which many attendees submitted questions.

While the FDA and OHRP share a mission in protecting volunteers in research, the FDA has a unique responsibility as a public health and consumer protection agency. The dual mission is reflected in the purpose for Investigational New Drug (IND) and Investigational Device Exemption (IDE) regulations which propose to assure safety and rights of subjects, permit evaluation of a drug’s safety and effectiveness, and encourage discovery and development of useful devices intended for human use. 

IRB review of FDA-regulated research requires the interpretation and application of regulatory standards that are different from and often in addition to those of the Common Rule. In 2013, FDA issued guidance to clarify that IRBs share the responsibility for reviewing investigator qualifications, research site adequacy, and verifying the determination of whether an IND or IDE is required for an FDA-regulated investigation.

From a practical standpoint, fulfilling these obligations requires an IRB to first recognize FDA-regulated research. To aid in this task, begin with regulatory definitions. While the definition of "research" and "human subject" are relevant for research regulated under the Common Rule, FDA has regulation-specific versions of the terms "clinical investigation", "human subject" and "test article"; all central to identifying FDA-regulated research.

Although this is a basic IRB task, navigating the gray areas or gaps in the regulatory framework can be challenging considering the wide range of products that may be considered “test articles”. Generally, "test articles" are intended to diagnose, cure, mitigate, treat, or prevent disease in humans, and articles intended to affect the structure or function of the body. But, be aware of FDA stated exceptions—such as the Dietary Supplement Health and Education Act of 1994 exception for select dietary supplement studies only assessing structure/function in healthy subjects or 21st Century Cures Act exceptions for select software functionsas well as instances where FDA plans to exercise enforcement discretion because known potential risks do not warrant compliance enforcement with applicable regulatory requirements.

Careful review of the study design and stated objectives can help differentiate use of a product vs. testing a product. Consider intent; current for determining if FDA-regulated and future for determining need for IND/IDE. Subtle nuances can make a difference. For example, a study would not be FDA regulated, if assessing a product’s effectiveness for a function other than to cure, treat, diagnose, prevent, mitigate or effect structure or function of the body.

Notice FDA's dual mission illustrated in existing guidance. Browse FDA warning letters for interpretation of boundaries and compliance. Absent specific instruction, consider and document the logic and thought process contributing to the IRB’s determination and where necessary, contact the agency for advice.

The webinar applied FDA's guidance on when IND/IDE regulations (21 CFR 312/812) apply to Real World Data studies, which is different from traditional investigations. I also reviewed the framework provided in FDA's policy on Software Functions including Mobile Applications and Digital Health. The following audience questions and responses further explore the nuances within the framework.

Q: Should an IRB consider a study testing feasibility of a "prototype" device to treat, cure, or mitigate a condition, as FDA-regulated?

A: According to FDA's IDEs for Early Feasibility Medical Device Clinical Studies guidance,

  • As with all clinical studies of investigational devices, an early feasibility study must comply with 21 CFR part 812 (IDE)
  • Any early feasibility study involving human subjects must comply with FDA human subject protection requirements, including obtaining informed consent and Institutional Review Board (IRB) (or ethics committee) oversight

Q: Would a study involving the on-label use of anesthetic for skin biopsies be considered "FDA-Regulated" if the anesthetic is not being tested, and the results of the research will not be reported to the FDA?

A: Based on the description provided, the study would NOT be FDA-regulated. The IND regulatory definition of clinical investigation excepts the use of a marketed drug in the course of medical practice. FDA repeatedly indicates in guidance that the agency has no intent to regulate "on" or "off-label" use within the practice of medicine. The same would apply for a study using a marketed device to elicit a physiologic response or measure a clinical outcome, where no data is collected on or about the device itself (e.g., an exercise study uses a standard marketed monitor to measure athletic performance, but the study is not collecting data to measure the safety or effectiveness of the monitor.

Q: In determining whether a study using real world data would need an IND or IDE, the FDA guidance differentiated between interventional and non-interventional studies where treatment decisions are based solely on clinical judgement. What about a predictive model developed only on retrospective clinical data, that will be used to determine treatment?

A: Since the question involves only retrospective data, use of the model to determine treatment is presumed to be a future use and not use during the study.

FDA's 2017 Real-World Evidence guidance specifies that an IDE would likely NOT be required, as long as the study does not impact how the device is administered, and the administration is within the normal course of medical care. For example, retrospective analyses of existing RWD evaluating an off-label use of a medical device would generally NOT be subject to IDE regulations. In such cases, treatment decisions were made in the best interest of patients according to their clinician’s medical judgment at that time. However, the guidance goes on to note that regardless of applicability of IND regulations (21 CFR 812), FDA regulations for IRB review (21 CFR 56) and Informed Consent (21 CFR 50) may apply.

Learn more about this topic at the 2022 PRIM&R Annual Conference (PRIMR22)! There will be an in-depth, half-day workshop on December 6 called Applying the FDA Framework in Conducting IRB Review, as well as time to connect with a panel of FDA representatives on December 14.


Belinda Smith, MS, RD, CCRC, is a research education specialist with 34 years of experience in human research, beginning with clinical research coordination and evolving into human subject protections. She currently oversees education and outreach for the University of Kentucky human research protection program. The UK Education Team utilize instructional design to create innovative education projects and initiatives. In addition, she provides FDA consultation for the Office of Research Integrity and Institutional Review Boards. She has co-authored publications and presented at national conferences in the areas of metabolic research, clinical research, and human research protection.

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