The Food and Drug Administration (FDA or "the Agency") announced on 14 July the publication of an anticipated draft guidance on in vitro companion diagnostic devices. The draft guidance document follows the Agency's 2005 concept paper, which outlined FDA's preliminary views on the appropriate regulatory framework for companion diagnostics.1 Stakeholders sharply criticized the 2005 concept paper as proposing unrealistic and inflexible regulatory requirements. In the draft guidance, FDA again outlines a policy position that if safe and effective use of a therapeutic product depends on a diagnostic device, then FDA generally will require approval or clearance of the diagnostic device at the same time that FDA approves the therapeutic product. That said, the draft guidance does allow for exceptions to the general rule of concurrent approval.


Proposed definition of "IVD companion diagnostic device": The draft guidance document defines an "IVD companion diagnostic device" as one that "provides information that is essential for the safe and effective use of a corresponding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." It is important to note that the proposed definition excludes devices that provide useful information regarding a product's use, if that information is not a "determining factor" in that therapeutic product's safety and efficacy. This proposed definition draws a regulatory distinction between tests that are intended as adjunctive tools in treatment decision-making (i.e., tests that are not "companion diagnostics") and those tests that are critical in determining best responders or identification of patients at risk for serious adverse reactions to a drug/biologic (i.e., companion diagnostics).

An IVD companion diagnostic device that supports the safe and effective use of a particular therapeutic product may be: (1) a novel IVD device (i.e., a new test for a new analyte), (2) a new version of an existing device developed by a different manufacturer, or (3) an existing device that has already been approved or cleared for another purpose.


Proposed review and approval process: For a new device, the Agency strongly recommends that a therapeutic product and its corresponding diagnostic device be developed and approved contemporaneously. According to the draft guidance, novel therapeutic products whose safe and effective use requires the results of a diagnostic test will not be approved unless FDA has determined that the IVD is "properly validated and meets the applicable standard for safety and effectiveness or for substantial equivalence for the use indicated in the therapeutic product's labeling." 

While FDA expects that a companion diagnostic device and the associated therapeutic product will be approved at the same time, there are certain circumstances in which the Agency might approve a therapeutic product before the companion diagnostic designated in its labeling is cleared or approved. Specifically, FDA indicated that it may approve a therapeutic product that is intended to treat a serious or life-threatening condition for which no alternative treatment exists and where the benefits of the use of the therapeutic product far exceed the risks that may be presented with use of that product without an approved or cleared companion IVD.


In addition, the Agency states that it may approve a revision to the labeling of an already approved therapeutic product when it is necessary to include use of an unapproved or uncleared companion diagnostic device to address a serious safety issue. The draft guidance explains that the review and approval of a companion IVD and the corresponding therapeutic product will be a collaborative effort of the applicable offices at FDA. Specifically, approval via a premarket approval application or clearance via a 510(k) premarket notification of the diagnostic device will be subject to the applicable medical device regulations and approval of the therapeutic product will be subject to relevant drug or biologic product regulations.


Importantly, the proposed guidance notes that studies of companion diagnostics used to make critical treatment decisions (e.g., patient or treatment decisions) likely will be significant risk devices that will require an Investigational Device Exemption (IDE) unless the device is used in a matter already cleared or approved by the Agency. FDA states in the draft guidance that the agency "strongly encourages" sponsors to request meetings "with both relevant device and therapeutic product review divisions as early in development as possible."


Labeling: The draft guidance outlines labeling requirements for therapeutic products and their associated companion tests. In general, the draft guidance indicates that FDA will require companies to list the type of companion IVDs in a therapeutic product's label, rather than the brand name of the test, to "facilitate the development and use of more than one approved or cleared" test for a specific indication. With regard to a companion IVD, the diagnostic test's label will have to list the specific drug/biologic or therapeutic class for which the diagnostic device is intended to be used. Any change in a diagnostic test's intended use (i.e., if the sponsor wants to market the test in a different disease setting or to determine response to other drugs/biologics) likely will require a new marketing application.


Laboratory developed tests: On a related note, the draft guidance document does not specifically address FDA's regulation of laboratory developed tests (LDTs). While it has been the Agency's position that CLIA (Clinical Laboratory Improvement Amendment) laboratories that develop LDTs are subject to FDA oversight, this is still an area of ambiguity without any clear guidance from the Agency. As such, FDA has not provided any guidance to industry regarding the specific regulatory requirements that will be applied to LDTs, including those that are offered by laboratories as a service in providing information about the safe and effective use of any therapeutic products. There is precedent for FDA allowing the labeling of therapeutic products for use with LDTs that have not been cleared or approved by FDA, but the draft guidance is unclear regarding whether FDA will allow this practice to continue.


Conclusions: The draft guidance has been long-awaited by industry, which has sought guidance in this area of device regulation. Thus far, the Agency has been working with sponsors of therapeutic product/diagnostic test combinations on a case-by-case basis, and based on the initial draft guidance document, it appears likely to continue to do so. Dr. Elizabeth Mansfield, Ph.D., Director of Personalized Medicine in the Office of In Vitro Diagnostics has been quoted as saying that the Agency is "not expecting to change [its] approach. This guidance is intended to let stakeholders know what [the Agency's] favored approach is so that their expectations are matched to the regulatory approach."2


The industry and the Agency have acknowledged that companion diagnostics are critical to the advancement of personalized medicine. However, given the different timelines associated with the development of drugs/biologics versus diagnostics, the general concurrent approval requirement outlined in the draft guidance could add significantly to the time required for commercialization of products (both drugs/biologics and diagnostics).


Public comments: FDA has opened a public docket for comments on this draft guidance and will be accepting comments until 12 September 2011. Stakeholders are encouraged to submit comments regarding this draft guidance. Electronic comments on Docket No. FDA-2011-D-0215 can be submitted at Written comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852.