All I Want for New Year’s is FDA IVD Guidance

You know you are a regulatory affairs geek when you find yourself on a Monday evening happily curled up on the couch with a warm blanket, a cup of hot cocoa, and new FDA draft guidance.

As we regularly provide guidance to clients developing or reviewing research protocols involving in vitro diagnostic devices (IVD) devices, Kinetiq pays close attention to the FDA’s interpretation of how investigational device regulations apply to IVDs. In December 2016, I hinted that the FDA was hard at work developing additional guidance on the topic. Just over a year later, the Agency finally released the document we have all been waiting for.


Highlights from the FDA’s Draft Guidance Holiday Surprise

The FDA notes that the growth of precision medicine has led to an increasing number of therapeutic product1 clinical trials that use investigational IVDs to guide subject management. IVDs used in such clinical investigations often generate information that directly influences the types of therapeutic product or therapeutic management strategies to which a participant might be exposed. As a result, if the IVD is investigational, its use may expose participants to significant risk. In a bit of a finger wag, the FDA expresses concern that sponsors and IRBs may not understand that many IVDs used in therapeutic product trials are investigational and may not adequately assess the risks associated with such IVDs. Thus, the guidance is intended to provide information about:

  • Definitions and concepts that are important in assessing investigational IVD risks
  • The roles and responsibilities of sponsors and IRBs in complying with investigational device exemption (IDE) requirements
  • FDA’s recommendations and requirements for submitting significant risk investigational IVD IDE applications


Investigational IVDs

A device is investigational if it is the “object of an investigation.”2 Investigation is defined as a “clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device.”3 While this seems straightforward, a point of confusion for many sponsors and IRBs is whether an unapproved IVD would be considered investigational if it is used to direct the management of subjects within a trial, but the IVD manufacturer does not intend to seek FDA clearance or approval for the commercial distribution of the IVD (e.g. prototype clinical trial assays).

In this guidance, the FDA clarifies that the agency considers an IVD to be investigational if it “used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product” (emphasis added). In other words, if any safety or effectiveness information data may be gleaned about the IVD, its use is investigational and IDE regulations apply.

The FDA further clarifies that an investigational IVD might be a novel IVD, an IVD that is legally marked in the U.S. for a different intended use, or a legally marked IVD that has been significantly modified. The intended use of an IVD in a therapeutic product trial depends on how that IVD is incorporated into the protocol. FDA emphasizes that changes to a cleared or approved IVD that would identify a new patient population or new specimen type would qualify as a new intended use.

This information provides much-needed clarification. However, the guidance does not explain how an IRB should assess whether a therapeutic product protocol is designed to obtain or may yield safety or effectiveness information about the IVD in question. In other words, should an IRB assume that the sponsor will obtain safety or effectiveness data about an IVD if it is using the IVD to guide the therapeutic management of subjects in a therapeutic product trial and that IVD is not approved or not used in accordance with the intended use and indication?

Additionally, it would be helpful if the FDA would clarify when an IVD is “used” for research. For example, FDA representatives have indicated elsewhere that an IVD is not investigational if the testing was done outside of the research, for clinical care purposes, and results are simply shared with the research team.

Assessing Risk

If an IVD is determined to be investigational, the next assessment is whether the IVD is exempt from IDE regulations, non-significant risk (NSR), or significant risk (SR). As discussed in last year’s article, many investigational IVDs will meet the FDA’s diagnostic device exemption criteria. Detailed information on exempt IVDs can also be found in the FDA’s 2010 FAQ Guidance.

This newest guidance provides additional information on how to assess the risk of a non-exempt investigational IVD used in a clinical investigation of a therapeutic product. The FDA emphasizes that the level of risk will mostly depend on the clinical consequences of erroneous or inaccurate results from the IVD. However, invasive sampling may itself also introduce significant risk. Sponsors and IRBs are therefore encouraged to consider the following factors when making a risk determination:

  • Will use of the results from an investigational IVD lead to some study subjects foregoing or delaying a treatment that is known to be effective?
  • Will use of the results from an investigational IVD expose study subjects to safety risks (e.g., adverse events from the investigational therapeutic product) that exceed the risk encountered with the control arm therapy or non-trial standard of care?
  • Is it likely, based on existing knowledge about the relationship between the biomarker and the investigational therapeutic product, that incorrect results from the investigational IVD would present a potential for serious risk to study subjects?
  • Does use of the investigational IVD require invasive sampling that is not part of standard of care?


Recommendations for IRBs and Sponsors in Evaluating Investigational IVDs

The FDA states clearly that sponsors should provide the IRB with an assessment of whether or not any IVD being used in a study is an investigational IVD, along with supporting information and an assessment of whether the IVD is exempt, NSR, or SR.

IRBs should request follow-up information if they believe that the sponsor did not identify or adequately describe the use of an investigational IVD and its associated risks in a trial. The guidance provides a list of seven questions IRBs should consider when reviewing applications for therapeutic product trials. These include questions guiding the IRB to evaluate whether each individual IVD used in a study is investigational; to consider whether the IVD is IDE exempt; to assess the risk of a non-exempt IVD; and to review the adequacy of informed consent documents.


Sponsor Recommendations

The guidance concludes with recommendations to sponsors for including investigational IVD information in the corresponding IND submission for the therapeutic product; managing IDEs and INDs for the same study; scheduling Q-submission meetings with the FDA to discuss IVD risk, study design, and regulatory requirements; and preparing IDE applications for SR investigational IVDs.

Of note, although the FDA acknowledges that IRBs are not involved in the review of an IDE application, the agency recommends that IRBs ensure an investigation involving a SR investigational IVD has an FDA-approved or conditionally approved IDE by obtaining a copy of FDA’s IDE approval letter from the sponsor.

The draft guidance does not answer all of our questions, but it does provide a thoughtful overview of the relevant regulatory framework as well as detailed information to help sponsors and IRBs evaluate IVDs used in clinical investigations of therapeutic product and determine the associated risks. Armed with this information, sponsors and IRBs should be better prepared to recognize when an IVD might be considered investigational and, when dealing with a significant risk IVD, to provide participants with important additional protections.

Comments and suggestions regarding this draft guidance can be submitted to


Executive Insight

Mitchell Parrish, JD, RAC, CIP, VP of Legal and Regulatory Affairs

IVDs are incredibly important. In some estimates, IVDs influence around 70% of medical decisions while only accounting for about 2% of healthcare expenditure in the U.S. In other words, IVDs provide bang for the buck. This is also true in clinical investigations, where IVDs have enabled significant advances. The FDA did not randomly issue its draft guidance on IVDs. The use of IVDs is widespread and the FDA is hoping for clearer application of those regulations intended to offer some protection to participants in clinical trials utilizing IVDs.



1 As used in the FDA’s guidance, “’therapeutic product’ includes therapeutic, preventive, and prophylactic drugs and biological products.” Note that this article uses the FDA’s terminology regarding “therapeutic” products; “patient” populations, and “treatment” assignment. I do not attempt to address here the FDA’s linguistic choices nor the arguably provocative implication that the agency considers precision medicine trials to be a form of medical treatment.

2 21 CFR 812.3(g).

3 21 CFR 812.3(h). Interestingly, the FDA notes in guidance footnote 12 that, for determining the applicability of the IDE regulations, the relevant definition of investigation is the one found in 21 CFR 812.3(h), not the definition at 21 CFR 56.102(c) (the regulations covering IRB requirements).

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