Introduction: The Food and Drug Administration (FDA or the agency) announced on July 31, 2014, the publication of a final guidance on in vitro companion diagnostic devices. This guidance finalizes a draft guidance document that the agency issued on July 14, 2011, which in turn followed the agency’s 2005 concept paper outlining the FDA’s preliminary views on the appropriate regulatory framework for companion diagnostics. Stakeholders sharply criticized the 2005 concept paper as proposing unrealistic and inflexible regulatory requirements, such as concurrent approval of therapeutic agents and companion diagnostic tests. The final guidance, nevertheless, embodies the FDA’s policy position that when safe and effective use of a therapeutic product depends on a diagnostic device, the FDA generally will require approval or clearance of the diagnostic device at the same time that the FDA approves the therapeutic product. That said, the guidance allows for two exceptions to the general rule of concurrent drug/device approval – when the therapeutic product is intended to treat serious and life-threatening conditions for which no alternative exists and when a serious safety issue arises for an approved therapeutic agent, and no companion diagnostic test is yet available. 

Definition of “IVD Companion Diagnostic Device:” Like the draft guidance document, the final guidance defines an “IVD companion diagnostic device” as one that “provides information that is essential for the safe and effective use of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.” It is important to note that the definition excludes devices that provide useful information regarding a product’s use when that information is not a “determining factor” in that therapeutic product’s safety and efficacy. This 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 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.

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 guidance, novel therapeutic products whose safe and effective use requires the results of a diagnostic test will not be approved unless the 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 the 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, the 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 final 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 the 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 biologics product regulations.

Importantly, the 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. The FDA states in the 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 guidance outlines labeling requirements for therapeutic products and their associated companion tests. In general, the guidance indicates that the FDA will require companies to list the type  of companion IVDs in a therapeutic product's label, rather than the brand names 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 (e.g., 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 guidance document does not specifically address the FDA’s regulation of laboratory developed tests (LDTs). The FDA has separately issued two draft guidance documents on July 30, 2014, about the agency’s proposed approaches and timing for LDT enforcement. However, the FDA has stated that LDTs that are offered as companion diagnostics will be considered high-risk devices that will require premarket review as well as other FDA regulatory requirements. A separate client update on the proposed LDT approach will be available shortly.

Conclusions: The final guidance is consistent with and reiterates FDA positions regarding companion diagnostics outlined (and informally enforced) since the July 2011 issuance of the draft guidance. During that time, the FDA has been working with sponsors of therapeutic product/diagnostic test combinations on a case-by-case basis, and based on the final guidance document, it appears likely the agency will continue to do so.

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 guidance could add significantly to the time required for commercialization of products (both drugs/biologics and diagnostics).