You should submit comments and suggestions regarding this draft document within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

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Table of Contents

    1. Novel Therapeutic Products
    2. Approval of a Therapeutic Product without an Approved IVD Companion Diagnostic Device
      1. New Therapeutic Products to Treat Serious or Life-Threatening Conditions
      2. Already Approved Therapeutic Products
    3. General Policies
    1. Therapeutic Product Labeling
    2. IVD Companion Diagnostic Device Labeling

Draft Guidance for Industry and Food and Drug Administration Staff

In Vitro Companion Diagnostic Devices

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

All diagnostic devices used to make treatment decisions in a clinical trial of a therapeutic product will be considered investigational devices, unless employed for an intended use for which the device is already approved or cleared. If used to make critical treatment decisions, such as patient selection, treatment assignment, or treatment arm, a diagnostic device generally will be considered a significant risk device under 21 CFR 812.3(m)(3) because it presents a potential for serious risk to the health, safety, or welfare of the subject, and the sponsor of the diagnostic device will be required to comply with the investigational device exemption (IDE) regulations that address significant risk devices. In such cases, FDA will expect the sponsor to conduct the trial under full IDE regulations.11

If a diagnostic device and a therapeutic product are to be studied together to support their respective approvals (or clearance as appropriate for the diagnostic device), both products can be studied in the same investigational study, if the study is conducted in a manner that meets both the requirements of the IDE regulations and the investigational new drug (IND) regulations (21 CFR Part 312).

Information about the planned use of an IVD companion diagnostic device and its use in clinical trials should be included in an investigational submission. This information will help FDA understand and provide advice on how the IVD device will be used to enroll subjects into the trial(s) and how the test will be validated for use. For therapeutic product INDs, the therapeutic product review center (Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research (CBER)) will engage appropriate expertise from the diagnostic product review center (Center for Devices and Radiological Health or CBER), and joint advice will be provided to the sponsor.

In addition, it will be helpful if both the IVD companion diagnostic device product sponsor and the therapeutic product sponsor submit information about the proposed IVD companion diagnostic device in a preIDE (a consultative submission designed to ensure that appropriate validation studies are planned and carried out) to the diagnostic review center. This will enable a more focused and in-depth discussion about the validation of the IVD companion diagnostic device and will aid in planning for a device PMA or 510(k) that is complete and timely. When appropriate, expertise from the relevant therapeutic review center will be included in the diagnostic review center meetings.

FDA strongly encourages sponsors considering developing either of the products discussed in this guidance to request a meeting with both relevant device and therapeutic product review divisions as early in development as possible.

1 As used in this guidance, therapeutic product includes therapeutic, preventive, and prophylactic drugs and biological products. Although this guidance does not expressly address therapeutic devices intended for use with in vitro diagnostics, the principles discussed in this guidance may also be relevant to premarket review of such devices.

2 Examples of currently approved IVD companion diagnostic devices that illustrate the importance of established performance parameters for both the therapeutic product and the IVD companion diagnostic device include FDA approved HER-2 testing to determine whether Herceptin (trastuzumab) therapy is indicated for treatment of metastatic breast cancer and gastric cancer. Herceptin lacks effectiveness in the HER-2 marker negative population, and also has the possibility of causing severe adverse effects. Therefore it is important to use an IVD companion diagnostic device to identify only those patients who could benefit from the therapy.

3 See 21 CFR 809.10 (b)(12).

4 In some cases, an IVD companion diagnostic device intended for use with a therapeutic product and that therapeutic product may together constitute a “combination product.” See 21 CFR 3.2(e)(3) and (4). Whether an IVD companion diagnostic device and therapeutic product would together, in fact, constitute a combination product should be determined on a case-by-case basis. Also, combination product status could affect regulatory requirements beyond the scope of this guidance. For additional information, please contact the Office of Combination Products or refer to their webpage on the Agency’s website at

5 Generally, this means that the use of the IVD companion diagnostic device with the therapeutic product allows the therapeutic product’s benefits to exceed its risks.

6 This may include identifying patients in a specific population for which the therapeutic is indicated because there is insufficient information about the safety and effectiveness of the therapeutic product in any other population. An example is a therapeutic that is indicated only for patients who by virtue of the presence of a marker in tumor cells are believed to be unlikely to respond to other therapies.

7 Examples of such tests are commonly used and well understood biochemical assays (e.g., serum creatinine or transaminases) used to monitor organ function. Note, however, that circumstances may occur when use of such tests, in the context of the therapeutic product, rises to an IVD companion diagnostic device level and approval or clearance for such use will be necessary. Note also that a novel IVD device providing information that is useful in, but not a determining factor for the safe and effective use of a therapeutic product, would not be considered an IVD companion diagnostic device.

8 To the extent an IVD companion diagnostic device and a therapeutic product together meet the definition of a combination product, a single application for the combination product may be submitted in some cases, though where appropriate, and the Agency may require separate applications for the constituent parts of the combination product. See 21 CFR 3.4(c).

9 Safety measures might include a risk evaluation and mitigation strategy (REMS), or a postmarket requirement, if necessary,

10 Experience indicates that most IVD companion diagnostic devices will be Class III devices, although there may be cases when a class II classification with premarket notification (510(k)) or other type of submission is appropriate.

11 Alternatively, if the IVD companion diagnostic device and therapeutic product are considered a combination product, FDA will expect the investigational device to be investigated under the IND for the therapeutic product.