On July 14, 2011, the FDA issued “Draft Guidance” relating to regulatory approval of in vitro companion diagnostic devices/tests, also called “IVD companion diagnostic devices.” The FDA intends the Guidance to assist those (1) who develop a therapeutic product that depends on the use of such a device/test for the product’s safe and effective use, and (2) who develop a companion diagnostic device intended for use with a corresponding therapeutic product.  The FDA invites comments and suggestions regarding the Draft Guidance within 60 days.

As background, the Draft Guidance notes that development of an increasing number of therapeutic products depends on the use of diagnostic tests to be safe and effective. Moreover, when diagnostic device results are a determining factor in patient health, the device must provide reliable results. The device cannot fail analytically (e.g., fail to accurately measure protein levels) or clinically (e.g., fail to identify patients accurately).

“IVD Companion Diagnostic Device” Defined

Consistent with its stated intentions, the Draft Guidance defines an “IVD companion diagnostic device” as one that “provides information that is essential for the safe and effective use of a corresponding therapeutic product.” In other words, the definition does not include a device that provides useful information regarding a product’s use, if that information is not a “determining factor” in that product’s safety and efficacy.

The Draft Guidance also notes that “ideally” sponsors will contemporaneously develop a therapeutic product and corresponding diagnostic device, as well as relevant clinical data for both. That said, the FDA recognizes that contemporaneous development is not always possible. Along these lines, an IVD companion diagnostic device may be (1) a new device, (2) a new version of existing device, or (3) an existing device approved/cleared for another purpose.

Review and Approval Process

For a new device, the FDA recommends that a therapeutic product and its corresponding device be developed and approved contemporaneously. In most cases, assuming device/test results are essential for product safety and efficacy, the FDA will not approve the product or use of the product with the device if the FDA has not also approved/cleared the device itself.

The Draft Guidance indicates, however, that the FDA has discretion to approve a therapeutic product for use with a companion device, even if the FDA has not yet approved/cleared the device. In this situation, the FDA expects it will approve/clear the device subsequently, and that sponsors will revise relevant therapeutic product labeling accordingly. The FDA will also consider whether additional protections are necessary.

In this context, the FDA refers to two scenarios where it may approve a therapeutic product for use with an unapproved/uncleared companion device: (a) a new product will treat a serious or life-threatening condition for which no satisfactory alternative treatment exists, and benefits from using the unapproved/uncleared companion device outweigh risks; and (b) an already approved product exists, but labeling for that product must be revised to address serious safety concerns, and use of an unapproved/uncleared companion device may address such concerns.

Generally, if safe and effective use of a therapeutic product depends on use of a companion diagnostic device, the device should be available once the FDA approves the product. Thus, the FDA will apply a “risk-based approach” to determine regulatory pathways for IVD companion diagnostic devices, where the levels of risk to patients and available controls to mitigate risks dictate whether the device will require PMA (premarket approval) or 510(k) clearance.

Except in certain situations, such as (a) and (b) discussed above, the FDA intends to approve/clear a therapeutic product and its corresponding companion diagnostic device at the same time. In this vein, the FDA encourages sponsors to time clinical studies and regulatory submissions to facilitate concurrent approval.

In a situation where a relevant device is already legally marketed, but the device manufacture intends to market the device for a new use as a IVD companion diagnostic device for a new therapeutic product, the FDA considers this to be “a major change in the intended use of the device, raising new questions of safety and effectiveness.” Thus, the FDA must approve/clear the new use of the device with the new product.


Regarding labeling of a relevant therapeutic product, the Draft Guidance notes that existing regulations (21 CFR 201.56 and 21 CFR 201.57) indicate that product labeling must include information relating to relevant laboratory tests. For example, if a therapeutic product is only safe and effective in a patient subpopulation identified by a diagnostic test, the Indications and Usage section of the labeling must define the patient subpopulation. Likewise, if a diagnostic test is essential for monitoring beneficial or adverse effects, the Warnings and Precaution section must identify the type of test. In addition, labeling must include information about the type of device (i.e., intended use of the device), rather than a specific manufacturer’s device. Also, if the FDA approves/clears a companion diagnostic device after it approves a relevant therapeutic product, sponsors must update product labeling accordingly.

Regarding labeling of IVD companion diagnostic device, the Draft Guidance states such labeling should specify the intended use of the device, as well as relevant therapeutic products. When appropriate, the labeling can name a class of therapeutic products, rather than specific products within the class. Device labeling should be expanded (i.e., approved/cleared) to reflect use in a new disease or setting, or with a different/new therapeutic product.

Investigational Use

The FDA will consider any diagnostic device used to make treatment decisions in a clinical trial to be an “investigational device,” unless the device is used in a matter already approved/cleared. A sponsor must comply with investigational device exemption (IDE) regulations that address significant risk devices, if one uses a diagnostic device to make critical treatment decisions, such as patent selection, treatment assignment, or treatment arm.

A diagnostic device and therapeutic product may be studied in the same investigational study, as long as the study otherwise meets IDE and investigational new drug (IND) regulations. Sponsors should include information about a planned use of an IVD companion diagnostic device and its use in clinical trials in an investigational submission. Further, “it will be helpful” if the device sponsor and the therapeutic product sponsor submit information about the proposed IVD companion diagnostic device in a preIND submission.

Lastly, the FDA “strongly encourages” sponsors to request meetings “with both relevant device and therapeutic product review divisions as early in development as possible.”

60 Days to Provide Comments to Draft Guidance

The FDA invites anyone to provide comments or suggestions to the Draft Guidelines within 60 days, i.e., by approximately Monday, September 12, 2011. The Draft Guidance itself states that this draft, “when finalized,” will represents the FDA’s “current thinking on this topic.” It does not bind the FDA or public. Thus, alternative approaches by sponsors and the FDA are likely possible.

Those in the field of personalized medicine, and especially current or potential sponsors of IVD companion diagnostic devices or relevant therapeutic products, may want to provide comments relating to concerns applicable to them and/or the industry overall, or at least monitor public comments provided by others. It is clear the FDA is listening.