FDA Issues Draft Companion Diagnostic Guidance; FDA Generally Will Require Approval or Clearance of Diagnostic at Same Time As Approval of Therapeutic if Safety and Efficacy of Therapeutic Depends on Diagnostic

By Jamie K. Wolszon –

FDA announced earlier this week the publication of a much-anticipated draft guidance on in vitro companion diagnostic devices.  In the draft guidance, FDA stakes out a policy position that if safe and effective use of a therapeutic depends on a diagnostic, then FDA generally will require approval or clearance of the diagnostic at the same time that FDA approves the therapeutic.  Companion diagnostics are key to the advancement of personalized medicine.  Some well-known companion diagnostics are the tests used to identify patients who will benefit from cancer therapy Herceptin.

FDA outlines two exceptions to this general rule: For new therapeutics, FDA may approve the therapeutic even though the companion diagnostic has not been approved or cleared if the therapeutic product is “intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared IVD companion diagnostic device.”

As for the second exception to the general rule, for therapeutic products that are currently on the market, FDA would be willing to approve a supplement for new labeling even without a cleared or approved companion diagnostic under the following limited circumstances: (1) The “labeling for an already approved therapeutic product must be revised to address a serious safety issue”; (2) the change made to address this issue requires use of a diagnostic test that is not yet approved or cleared; and (3) “the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared IVD companion diagnostic device.”

The guidance did not provide examples of types of therapeutics or diagnostics that would qualify for these exceptions from the general rule.

The guidance defines IVD companion diagnostic as “an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.” 

FDA provides as an example of an IVD companion diagnostic tests that “identify patients who are most likely to benefit from a particular therapeutic product.”  Companion diagnostics also include tests that “identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic product” and “monitor response to treatment for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness.”

Companion diagnostics do not include tests intended to provide “information that is useful to the physician regarding the use of a therapeutic product, but that are not a determining factor in the safe and effective use of the product.”  For instance, biochemical assays (e.g., serum creatinine tests) used to monitor organ function are not companion diagnostics.

Ideally, according to FDA, a “therapeutic product and its corresponding IVD companion diagnostic device would be developed contemporaneously, with the clinical performance and clinical significance of the IVD companion diagnostic device established using data from the clinical development program of the corresponding therapeutic product.”  However, FDA states that it recognizes that this will not always be possible.  This expectation that the therapeutic and the companion diagnostic would be developed contemporaneously may be viewed as unrealistic.

The guidance also notes that studies of companion diagnostics generally will be significant risk devices that will require an IDE.  Most studies of other IVDs are non-significant risk.

FDA will use a risk-based approach to regulate companion diagnostics.  FDA says that in its experience to date, companion diagnostics generally will be Class III devices requiring a PMA, but there could be instances where 510(k) would be sufficient.

The guidance recommends that sponsors consult with both the device center, for a pre-IDE meeting, and the center in charge of regulating the therapeutic component.  FDA notes that it is “developing appropriate internal policies and procedures to ensure effective communication among the relevant centers and to promote consistent and efficient product review.”  FDA also states that there could be instances where viewed as combination product and thus only one application but did not state what such instances would be. 

The guidance also discusses FDA’s view of the need for cross-labeling between the therapeutic and the companion diagnostic.

The guidance has been long-awaited by industry, which has sought guidance in this area – an area that has been marked by ambiguity.  Years ago, FDA issued a draft guidance on the topic, which received criticism from industry.  FDA stated last year that it would promulgate two guidances to provide clarity that would address issues including when FDA would require simultaneous approval and what data requirements the agency would require. 

The comment period for the draft guidance will close within 60 days of issuance, which occurred July 14.