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FDA Reinforces Common Key Regulatory Principles for Industry in CDx, Draft LDT Guidances


NEW YORK (GenomeWeb) – In finalizing the companion diagnostics guidance last week, the US Food and Drug Administration has maintained the same intent and much of the text from the draft version in laying out regulations for developing tests that are "essential" for the use of certain drugs.

Despite this, the document has added significance in the context of FDA's LDT guidance, a draft of which the agency last week provided to the US Congress for a first look (see related stories, here and here).

In the two documents, the FDA reinforces key regulatory themes, such as the importance of a test's intended use and risk in setting the pre-market requirements it has to meet. Additionally, in both guidances the agency exhibits flexibility toward tests for rare diseases where there is an unmet need and no other alternatives.

Flexible approach

The main tenets of the final guidance reinforce ideas that the agency has been promoting for years, mainly that the FDA prefers, whenever feasible, the simultaneous development and review of a drug and its companion test. A CDx, as defined in the guidance, is an in vitro diagnostic that provides "essential" information for the safe and effective use of a therapeutic, such as which patients benefit from the drug or are at increased risk for adverse reactions, safe dosages or when a drug should be stopped, and the identification of patients in whom the drug has been "adequately studied."

"If FDA determines that an IVD companion diagnostic device is essential to the safe and effective use of a novel therapeutic product or indication, FDA generally will not approve the therapeutic product or indication if the IVD companion diagnostic device is not approved or cleared for that indication," the agency states in the guidance.

A CDx will require premarket review, but whether the test developer will need to submit a premarket approval (PMA) application or for 510(k) clearance, depends on the intended use and risk of the test. "FDA will apply a risk-based approach to determine the regulatory pathway for IVD companion diagnostic devices, as it does with all medical devices," the agency said in the guidance. "This means that the regulatory pathway will depend on the level of risk to patients, based on the intended used of the IVD companion diagnostic device and the controls necessary to provide a reasonable and necessary assurance of safety and effectiveness."

This portion of the CDx final guidance reflects the sentiments that the agency expresses in its draft LDT guidance. Furthermore, in its oversight plan for LDTs, FDA said it will focus on bringing into compliance first and foremost lab tests with the same indication as FDA-approved or cleared companion diagnostics. The agency considers these tests to pose the highest risk to patients' health, since they are used to determine whether or not a person receives a drug or the amount of drug administered to the patient.

The agency goes on to acknowledge that there are scenarios where the simultaneous co-development of a drug and test is not possible. For example, the FDA said it won't hold up approval for a drug for a serious or life-threatening condition where no alternative therapy exists, due solely to the lack of an approved companion test. Even in such instances, the agency through its LDT guidance has tried to ensure that labs can't simply introduce a new CDx on the market without meeting certain regulatory requirements establishing the test as safe and effective.

"The codevelopment final guidance again asserts FDA's position that the agency will not keep a new therapeutic from the market if it is designed to address unmet needs for a serious and life threatening condition if the diagnostic kit is not yet cleared by the agency at the same time as the therapeutic is ready to be cleared," Amy Miller, executive VP at the Personalized Medicine Coalition, told PGx Reporter. "That's great news for drug companies"

Coordinating reviews

Thirteen pages long, the final CDx guidance is as simple and straightforward as regulatory guidances get. The main take away from the guidance for industry is that the agency favors, whenever possible,simultaneous Rx/Dx development and review – an idea the agency repeats throughout the document in different ways.

Still, one area that industry players may still have questions about is who is holding the reigns in involving and organizing the different industry and regulatory players around a particular drug/test program. "PMC's critique of the first [draft of the] companion diagnostics guidance was that there wasn't enough detail," particularly "on who coordinates the activities of co-development reviews," Miller said. "Is the onus on the FDA, the drug company, or the device manufacturer? Logically, it's the FDA, but is it the device center or the drug center that leads."

In the final guidance, the agency generally discusses coordinated reviews between its device and drug divisions in the section titled "investigational use." Drug sponsors and developers of companion tests are required to file for an investigational device exemption (IDE) before a CDx can be used in human clinical trials alongside a drug. But the FDA advises drug makers to discuss with the agency whether information about the CDx should be included in the investigational new drug application or separately in an IDE.

Similarly, the agency encourages both the drug and test developers to engage in discussions with FDA's diagnostic review center when forming the development plan for a CDx and ahead of submitting a premarket application or 510(k). "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," the agency notes in the guidance. "When appropriate, expertise from the relevant therapeutic product review center will be included in the diagnostic review center meetings."

"FDA likely has internal procedures in place to ensure that the therapeutic and the companion diagnostic move through [the agency] in a coherent fashion together, yet the final guidance is light on details," Miller said. "For example, FDA has been very creative and swift in regulating diagnostics being developed alongside therapeutics that have earned a breakthrough designation by the agency."

Finally, in case industry players didn't know it, the FDA closes the guidance with the most important piece of advice it has been giving out for the last few years: "FDA strongly encourages sponsors developing products discussed in this guidance to request a meeting with both relevant device and therapeutic product review divisions as early in development as possible."