The pilot program aims to publish minimum performance standards for a companion diagnostic (CDx) based on the clinical trial assay’s (CTA’s) performance during the drug product’s pivotal clinical trial. The timing of this pilot’s launch alongside FDA’s plans to publish a proposed rule to “make explicit” FDA’s authority over laboratory developed tests (LDTs) shows the agency’s focus on addressing perceived safety risks related to LDTs.

As described in the 2014 FDA guidance “In Vitro Companion Diagnostic Devices,” an in vitro companion diagnostic test or device (CDx) “provides information that is essential for the safe and effective use of a corresponding therapeutic product.” Generally, a CDx should be granted marketing authorization contemporaneously with the approval of the corresponding therapeutic product for the use indicated in the therapeutic product labeling. However, FDA may decide to approve a therapeutic product even if, at the time of the therapeutic product’s approval, an in vitro CDx has not yet received marketing authorization, when:

1. the therapeutic product is intended to treat a “serious or life-threatening condition,”

2. “no satisfactory alternative treatment exists” for that condition, and

3. the benefits from the use of the therapeutic product are so pronounced as to outweigh the risks from the lack of an in vitro CDx with marketing authorization.

In recent years, the use of companion diagnostics has increased with the proliferation of targeted therapies, especially in the oncology space. As a result, FDA has been exercising its discretion by approving some oncology drug products that require use of an in vitro CDx without contemporaneous marketing authorization of the test based on the principles listed above. In those cases, laboratory developed tests (LDTs) [1] are being used for patient treatment decisions, in order to fill the gap until the corresponding CDx is approved.

Historically, FDA has exercised enforcement discretion for LDTs; however, FDA has now announced plans to pilot a new approach that aims to provide greater transparency regarding performance characteristics that certain tests for oncology biomarkers should meet. In announcing the oncology pilot program, FDA expressed concerns about the reliability of LDTs, which do not require premarket authorization from FDA, but are separately regulated through Center for Medicare and Medicaid Services oversight of clinical laboratories. The agency has stated that it hopes the new program will help regulators have more confidence in future drug-device oncology combination products.

In the initial phase of the pilot, FDA intends to accept up to nine sponsors of CDER-regulated oncology drug products for which FDA determines that:

1. use of an in vitro diagnostic test is needed to identify the intended patient population,

2. no satisfactory alternative treatment exists, and

3. the anticipated benefits from the use of the drug product are so pronounced as to outweigh the anticipated risks from approval of the drug product without an FDA-authorized CDx.

To be accepted into the pilot program, FDA must also determine that the corresponding clinical trial assays (CTAs) a) use the same technology as a previously FDA-authorized CDx for any indication, (b) for which there is a well-validated reference method, well-validated comparator method, and/or well-characterized materials that can be used to support test accuracy.

According to FDA, the primary benefit of enrollment in this program is that, if selected, FDA will collaborate with each sponsor to provide feedback in the form of recommended minimum validation and performance characteristics for CTAs to be used to enroll subjects in the drug product’s pivotal clinical trial(s), prior to the start of the trial. In addition, if and when the drug is ultimately approved, FDA will recommend minimum performance characteristics for in vitro diagnostic tests to be used with the approved oncology drug product, based upon submission of data and information regarding performance of the CTAs actually used in the clinical trials that supported the drug’s approval. Going further, through the pilot program, LDT developers will be able to leverage the clinical validity of the CTAs established through the drug trial to help streamline validation of additional tests for the same use.

Next steps

FDA is now accepting “statements of interest” to apply for the oncology companion diagnostic pilot program, which may be submitted alongside a sponsor’s Investigational New Drug (IND) application, New Drug Application (NDA), or Biologic License Application (BLA). FDA has made available on CDRH’s website a series of templates that oncology drug product sponsors who have submitted the “statement of interest” may use to facilitate the provision of performance characteristic and validation information for CTAs used in the pivotal clinical trial(s) for the drug product. FDA also said it will publish the minimum performance characteristics for tests used with approved drugs in the pilot program.

Going beyond this pilot program, we anticipate FDA will continue to pursue legislative and other regulatory fixes for LDT regulations. Although Congress has not yet enacted the Verifying Accurate Leading-edge IVCT Development (VALID) Act, which would codify a framework by which FDA could regulate LDTs, FDA officials have made statements regarding their intent to promulgate new rules for LDTs through notice-and-comment rulemaking. Indeed, FDA’s latest Unified Agenda lists as a “significant” priority the goal of issuing a proposed rule to “make explicit” FDA’s authority over LDTs.