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Using NGS as CDx Will Require Paradigm Shift, Regulatory Changes, According to Experts at AACR

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Next-generation sequencing holds promise for use in companion diagnostics, but will require a paradigm shift as well as changes to the regulatory landscape, according to a number of experts that presented at last week's American Association for Cancer Research meeting in San Diego.

"We're in the era of 'here are my genes, what is my drug?'" said Laura van 't Veer, associate director of applied genomics at the University of California San Francisco's Helen Diller Family Comprehensive Cancer Center, in a presentation at the AACR meeting. Using DNA or RNA in companion diagnostics is now possible, she said, but "the question is, how do we implement it?"

Although a number of pharmaceutical companies are now using next-generation sequencing for biomarker discovery, they have been cautious about implementing the technology in clinical trials or as a tool for companion diagnostics. Amgen became an early adopter of the technology this year when it said it intended to develop a companion diagnostic based on next-generation sequencing for its colorectal cancer drug Vectibix (panitumumab).

The pharmaceutical company will work with Illumina to develop a test based on the company's MiSeqDx instrument, which received US Food and Drug 510(k) clearance last year.

The test will use sequencing to analyze the RAS family of genes, since mutations in those genes affect colorectal cancer patients' response to Vectibix.

However, no other drug company has yet indicated plans to develop NGS-based companion diagnostic tests.

"The reality is, the conceptualization of individual companion diagnostics is untenable," said Richard Klausner, chief medical officer at Illumina. The problem is that not only are there multiple drugs for any given target, but there are different diagnostic tests associated with different approved drugs that are all for the same target, he said. This paradigm is "unwieldy and unworkable."

Elizabeth Mansfield, director of personalized medicine at the FDA, said during a presentation at the conference that there is a need to move beyond the current companion diagnostics paradigm. For example, in non small-cell lung cancer alone there are multiple drug/test combinations that have been approved, but running each test "doesn't make a lot of sense," she said.

As opposed to one test for one target, next-generation sequencing offers the potential to have a panel of companion diagnostics in one test. For instance, she said, an NGS panel could assess all approved drug/target combinations for one histology. Another option, she said, would be to have a panel include not only analytes for approved drugs, but those for investigational drugs to determine potential clinical trials a patient may be eligible for.

However, Mansfield said that in order for such a test to be feasible in the clinic and pass regulatory muster, there must be standards. Currently, running four different commercial tests on the same tumor will give you four different answers, "so there are some regulatory controls that should be put in place," she said. Laboratories running such tests must be able to provide comparable results. "Sequencing is not yet trivial," she said.

Additionally, changing the current paradigm of companion diagnostic testing to include multiplex tests, such as those that run on next-gen sequencing systems, will require sponsors to come forward, Mansfield added. Thus far, she said the FDA has not yet evaluated an NGS instrument or assay for tumor tissue.

When the FDA cleared the MiSeqDx, it gave it a Class II exempt status, meaning that other companies developing systems with the "same intended use" do not have to go through the same 510(k) clearance process, but have to abide by special controls the FDA put in place. For instance, Life Technologies has said it plans to register its Ion Torrent PGM with the FDA this year. However, MiSeqDx's use is currently limited to targeted sequencing of DNA from blood, and sequencing tumor tissue would not fall under the same intended use, according to Mansfield.

For a sponsor to get a cleared NGS-based companion diagnostic test, it would have to submit the assay, including the software to add tumor sequencing to the intended use of the platform, Mansfield said.

She added that the FDA is open to receiving companion diagnostic submissions based on sequencing platforms. "I can envision [NGS panels] being used as standard oncology patient care," she said.

Illumina has indicated it is considering this option. Last year, an Illumina official spoke at the Hanson Wade NGS for Cancer Drug Development conference in Boston about partnering with pharmaceutical companies to design companion diagnostic tests under strict product development processes and running them as part of a clinical trial by partnering with a clinical research organization.

And at this month's AACR meeting, Klausner said that Illumina has been in discussions with the FDA about developing a broad oncology panel that would test a suite of genomic markers related to specific drugs. "We all see that the current system needs to evolve to follow what makes sense about the disease," he said.

Klausner said that Illumina is interested in working with the pharmaceutical industry to develop "universal panels that would cover every analyte." He suggested the panels be open and not owned by any particular company.

Illumina and the pharmaceutical companies would have to come up with performance standards for such tests, he added. And the success of bringing such panels through regulatory approval would depend on changes in the regulatory pathway. Regulatory agencies would have to address the challenges of analyzing technology that is far superior to previous technologies and so does not have a "gold standard" with which to compare it.

Additionally, measures would have to be put in place to address the fact that sequencing technology evolves quickly. Protocols must be locked down for the clinic, he said, but there should also be methods of enabling technology evolution without doing more prospective trials. "There is a need for standards," he said.

For its part, the FDA appears open to changes in how companion diagnostics are developed and regulated. "The FDA is ready," Mansfield said. "We are determined to make this move forward."

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