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FDA's Rx/Dx Draft Guidance Urges Simultaneous Development, but Addresses Alternative Scenarios

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By Turna Ray

A long-awaited
draft guidance issued by the US Food and Drug Administration this week clarifies which in vitro diagnostics fall into the agency's definition of a companion test and outlines various drug/diagnostic codevelopment scenarios in which the agency would allow sponsors to market tests that don't have 510(k) clearance or premarket approval.

The draft guidelines reinforce advice that agency officials have been providing through informal channels for some time now: that a drug and its companion test should ideally be developed simultaneously; that a treatment that depends on the use of a diagnostic test have a 510(k) cleared or premarket-approved test available for use once the drug is approved; and that drug and diagnostic companies should meet with the agency early and often to figure out the clinical validation requirements they need to fulfill for the development of a companion test.

For the most part, the "FDA intends to review each IVD companion diagnostic device submission within the context of, or in conjunction with, its corresponding therapeutic product, and FDA review of the test/therapeutic product pair will be carried out collaboratively among relevant FDA offices," the agency states in the draft guidance, though it acknowledges that there may be special instances when simultaneous Rx/Dx development may not be possible.

For example, the guidance cites Rx/Dx codevelopment situations in which a drug for a serious or life-threatening condition may be approved before a test is cleared through the agency or new data emerges suggesting the need for a companion test for a drug already on the market. In these instances, the companion test will still need to be reviewed and cleared by the FDA, but in the interim the agency will not restrict the market availability of the therapeutic or unapproved tests.

The guidance also outlines labeling requirements for drugs and their companion tests. Generally, the FDA will list a category of companion IVD in a drug's label, rather than a specific test, to "facilitate the development and use of more than one approved or cleared" test for the indication. In the case of a companion IVD, the test's label will list the specific drug or therapeutic class for which the test is meant to be used.

Any change in the test's intended use — for example if the sponsor wants to market the test in a different disease setting or to gauge response to other drugs — will require a new PMA or 510(k) submission.

Alberto Gutierrez, director of the Office of In Vitro Diagnostics in FDA's Center for Devices and Radiological Health, had previously stated that while a companion diagnostic draft guidance would be issued this year, the release of a separate guidance on Rx/Dx codevelopment will take much longer (PGx Reporter 12/08/2010).

"The Rx/Dx codevelopment guidance has not been released," an FDA spokesperson told PGx Reporter this week. "This is just the companion diagnostics guidance" that includes input from the FDA's Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and CDRH.

The FDA has said it intends to issue guidelines addressing aspects of drug/diagnostic codevelopment since 2005, when the agency issued a "concept paper" outlining its initial thinking on the topic. However, that effort was criticized by both pharmaceutical firms and test makers, which felt that the agency's proposed guidelines were too idealistic and failed to account for the challenges of aligning competing interests, different development timelines, and divergent regulatory pathways for therapeutics and diagnostics.

According to the agency, this guidance is part of an effort to address the increased use of diagnostics to predict which patients will respond to a drug. The public will have 60 days to comment on this draft document.

What is a Companion IVD?

The FDA defines an IVD companion test as a diagnostic device that "could be essential for the safe and effective use of a corresponding therapeutic product." Such a test can be used to identify patients most likely to benefit from treatment with a particular drug; gauge which patients are at increased risk for serious drug-associated adverse events; or monitor patients' responses to a treatment in order to adjust the dose or stop administration.

In a footnote, the agency further clarifies that "a novel IVD device providing information that is useful in, but not a determining factor for the safe and effective use of a therapeutic product, would not be considered an IVD companion diagnostic device." This draws a regulatory distinction between tests that the FDA has approved as adjunct tools in treatment decision-making and those tests that are critical in gauging best responders to a drug. In assessing whether a test is a companion IVD, one must carefully analyze the nuanced labeling language in FDA-approved products.

For example, genetic tests to predict which patients are at increased risk for experiencing adverse reactions to the anticoagulant warfarin — even those that have been cleared by the FDA — would not be considered companion IVDs under the definition in the draft guidance.

In 2007, FDA updated the labeling for warfarin to inform patients and doctors that people with variations in CYP2C9 and VKORC1 genes may respond differently to the drug. Then in 2010, the agency updated warfarin's label again with pharmacogenomically guided dosing ranges. However the labeling language for warfarin only recommends genetic testing in this setting; genetic testing is not required by the FDA (PGx Reporter 02/03/2010).

"For warfarin, the testing does not meet the definition of a companion diagnostic because the drug is considered safe and effective without the test," the FDA spokesperson said.

In another scenario, the label for the anti-platelet drug Plavix recommends the use of a companion test, but the FDA hasn't yet green-lighted a Plavix PGx test.

The agency updated the labeling for this drug last year to note that patients with diminished CYP2C19 function are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention. The label further indicates there are available tests "to identify a patient's CYP2C19 genotype [that] can be used as an aid in determining therapeutic strategy" (PGx Reporter 03/17/2010).

There are several laboratory-developed tests to gauge CYP2C19 SNPs associated with Plavix response. In addition, AutoGenomics gained 510(k) approval for its Infinity CYP2C19 Assay late last year and Nanosphere is currently in the process of seeking a premarket approval for its CYP2C19 test, which would allow it to include Plavix in the test's label (PGx Reporter 6/22/2011).

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However, the FDA doesn't endorse these tests as companion IVDs intended to predict best responders to Plavix. "The drug label change was considered to be critical enough to move forward without an approved test," the FDA spokesperson explained.

Different Rx/Dx Scenarios

Although simultaneous Rx/Dx codevelopment and regulatory review is the ideal situation, according to FDA, the draft guidance accommodates scenarios in which a drug might be available before the agency approves a companion test, or vice versa.

"FDA may decide to approve a therapeutic product even if its IVD companion diagnostic device is not yet approved or cleared when the therapeutic product is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists," the FDA states in the guidance, adding that in such a case the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device must outweigh the risks from having access to no companion test at all.

Additionally, the FDA also recognizes in its guidance that there may be instances when "the labeling for an already approved therapeutic product must be revised to address a serious safety issue and that the change made to address this issue may stipulate use of a diagnostic test that is not yet approved or cleared." In such a case, "if 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, FDA does not intend to delay approval of changes to the labeling of the therapeutic product until the IVD companion diagnostic device is approved or cleared," the agency states in its draft guidance.

The latter clarification is particularly significant for situations in which genomic data identifying a best-responder subpopulation emerges after the drug has been on the market for some time, since it would allow regulation to catch up with advancing science without restricting patient access to critical medications.

This is the scenario that Qiagen is in with its KRAS test to gauge best responders to colorectal cancer monoclonal antibodies.

In 2009, the FDA updated the labeling for two colorectal therapies already on the market, Amgen's Vectibix and Merck's Erbitux, to inform doctors that patients with KRAS mutations would not respond to these drugs. Subsequently, Qiagen's DxS subsidiary inked deals with both of these sponsors to develop companion tests for Vectibix and Erbitux, and the sponsors have been working with the agency to gain FDA's go-ahead for the KRAS companion tests (PGx Reporter 07/22/2009).

To date, the agency has not approved Qiagen's KRAS test. In the meantime, a number of laboratories are marketing tests that detect KRAS mutations but have not been cleared through the agency.

The language in the draft guidance suggests that the FDA regulations would accommodate a situation in which unapproved companion tests would be allowed to remain on the market while the agency reviews data submitted by the sponsors for an FDA-approved test.

But there may be limits to this allowance. FDA recently released a draft guidance barring the marketing of research-use only and investigational-use only IVD products for clinical diagnosis of patients (PGx Reporter 06/08/2011), which would restrict sponsors from selling RUO/IUO-labeled IVDs as companion tests. However, in the draft companion diagnostics guidance, the FDA specifies that sponsors must comply with investigational device exemption rules in order to use non-FDA approved companion IVDs to make treatment decisions or select patients in clinical trials.

Meanwhile, before the FDA released its draft guidance on companion diagnostics, the agency had announced its intent to promulgate new regulations for LDTs, which traditionally have been under the purview of the Centers for Medicare & Medicaid Services. Ahead of any regulatory guidance from the agency on LDTs, it appears that laboratories will be able to continue to market LDTs that gauge treatment response.

"This guidance is not related to LDTs," the FDA spokesperson told PGx Reporter. "At this time, the FDA will continue to exercise enforcement discretion on LDTs."

The FDA spokesperson added that the agency is "exercising enforcement discretion over KRAS tests" for the time being, and that "this practice will likely continue with LDTs for KRAS even when we have an approved test, until the agency outlines its framework for LDTs."

The agency hasn't promulgated any regulations or guidance changing the current system of oversight for LDTs, and as such, the FDA appears to be working within the existing regulatory framework to regulation companion diagnostics. On the one hand, FDA is allowing LDTs to be marketed as companion tests but is also leaving itself room to regulate LDTs it deems to be devices requiring FDA approval or clearance.

According to criteria outlined in the guidance, labeling for a drug that is dependent on a companion diagnostic must include information on the specific tests necessary for patient selection; mention dosage modifications for subpopulations; and identify any LDTs helpful for predicting patient response or adverse drug reactions.

Additionally, the agency's definition of companion IVDs "does not include … clinical laboratory 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." Examples of such tests, according to the FDA, include "well understood" biochemical assays for monitoring organ function, such as tests to gauge serum creatinine or transaminase levels.

The guidance does not mention any molecular IVDs in this example, but the FDA warns industry that "circumstances may occur when use of [a clinical lab test], in the context of the therapeutic product, rises to an IVD companion diagnostic device level and approval or clearance for such use will be necessary."


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