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FDA Releases Guidance Outlining Considerations for CDx Labeling for Oncology Drug Groups

NEW YORK – The US Food and Drug Administration on Monday released guidance outlining how developers of companion diagnostics for personalizing cancer therapies can broaden the indication for a test so that it references a group of similar drugs instead of a specific treatment. 

Companion diagnostics are defined by the FDA as tests that are required for the safe and effective use of a drug. In a 2014 guidance, the agency told diagnostics developers that companion diagnostic can be indicated for a group of therapeutic products, instead of a particular drug, if there is sufficient data to support such labeling. 

However, the pathway as to how to achieve such labeling hasn't been clear, and historically, the FDA has tended to approve CDx labeling that describes an intended use with a specific drug.  This has resulted in a patchwork of approvals where some tests can be used to identify best responders to certain drugs but not others with the same indication.

For example, the FDA has approved four companion diagnostics and five EGFR inhibitors for non-small cell lung cancer patients with EGFR exon 19 deletions or exon 21 (L858R) substitutions. Qiagen's Therascreen EGFR RGQ PCR Kit is indicated for use with afatinib (Boehringer Ingelheim's Gilotrif), gefitinib (AstraZeneca's Iressa), and dacomitinib (Pfizer's Vizimpro). Roche's Cobas EGFR Mutation Test V2 is indicated for use with gefitinib, erlotinib (Genentech's Tarceva), and osimertinib (AstraZeneca's Tagrisso). Thermo Fisher Scientific's Oncomine Dx Target Test is indicated for use with gefitinib. And Foudnation Medicine's FoundationOne CDx is indicated for afatinib, gefitinib, erlotinib, and osimertinib.  

This can be confusing for oncologists and necessitate additional tumor sampling, which is not ideal for patients. In the EGFR inhibitor example, "the oncology community would be better served by a companion diagnostic that detects EGFR exon 19 deletions or exon 21 (L858R) substitution mutations indicated for 'identifying patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and are suitable for treatment with a tyrosine kinase inhibitor approved by FDA for that indication,'" The FDA said in the guidance. "This could enable greater flexibility for clinicians in choosing the most appropriate therapeutic product based on a patient’s biomarker status."

Additionally, a more broadly labeled companion test would reduce the regulatory burden for labs and increase its utility. For example, if a CDx is already indicated for an oncology drug group, the sponsor could leverage the validation data when a new drug comes to market in that group. Moreover, the FDA pointed out that a CDx with broad intended use could be used in clinical trials for drugs that would potentially fall in the indicated therapy group.

A therapeutic group is defined by the FDA in this latest guidance as a group of drugs that have the same indication, "including the same molecular alteration(s), such as mutation(s), amplification(s), and fusion(s)." For each drug in the group, at least one device must have been used to establish its activity in the molecularly defined indication using the same specimen type.

Test makers' bid for broader labeling will have to be supported by evidence, however, and it won't be as easy as matching up diagnostic and therapeutic targets, the agency noted in the guidance. "Different diagnostics for the same target may utilize different cut-offs, filters, or other design features that impact the patient populations they identify and, consequently, the likelihood of a biomarker-positive patient to respond to a given therapy," the agency said. "Any potential differences should be evaluated to ensure it is clinically appropriate to take a broader labeling approach."

Diagnostics developers should keep these differences and other considerations in mind when developing the regulatory plan for their companion tests. To start, test developers should carefully define the therapeutic group that the test will be indicated for, keeping in mind that as new evidence comes to light the biomarker indication for therapeutic group may change. For example, the indication for EGFR monocolonal antibodies, cetuximab (Lilly's Erbitux) and panitumumab (Amgen's Vectibix) changed in a span of a few years from being limited in KRAS-muted colorectal cancer to being indicated for RAS-wild type CRC.

Test developers should also understand the mechanism of action for a group of drugs that will be administered with the help of a particular CDx, as well as the interaction between the biomarkers of interest and the drugs at the molecular level. This may require clinical studies, retrospective analysis of clinical trials, and nonclinical data. Sponsors could draw on the published literature to facilitate this understanding, product labeling or therapeutic study data, or conduct the studies themselves.

Additionally, the agency said it will want to see that a companion diagnostic has "sufficient and consistent experience" with a group of oncology drugs for the same biomarker-defined indications. At least two FDA-approved drugs with the same indication would satisfy this requirement. If the therapy group is indicated for a range of biomarkers, then the sponsor will need to show analytical validity for these markers. The FDA has already approved multi-marker companion diagnostics and the sponsors of these tests can leverage the data they've already generated to garner a broader label.

In terms of clinical validity, test developers that don't already have a companion diagnostic approved for a specific drug in a potential therapy group, may perform concordance studies with a CDx that's already approved or retrospectively analyze samples from patients treated with these drugs to demonstrate comparable efficacy. Sponsors could also do a clinical study to validate the link between the test and the patient outcomes in a specific drug indication.

The FDA encouraged sponsors interested in broadening CDx indications to an oncology therapy group to contact its drug and device divisions and discuss a regulatory plan. Such labeling will require a 510(k) or premarket approval application for new tests or a supplemental filing to expand the labeling of an already approved or cleared CDx. Additionally, the agency said it intends to update its webpage for FDA-approved CDx products, when a test achieves labeling for oncology therapeutic group.