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With Companion Dx Guidance Nearing Release, FDA's Mansfield Offers Some 'Provisional' Advice

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By Turna Ray

BETHESDA, Md. ─ The US Food and Drug Administration's long-awaited companion diagnostics guidance is in the "sign-off" stage at FDA's Center for Devices and Radiological Health, an agency official said this week.

Without speculating on a specific release date for the draft guidance, which the FDA has been working on since the release of a white paper in 2005, Elizabeth Mansfield, director of personalized medicine at the Office of In Vitro Diagnostics in FDA's CDRH, said the document is "definitely moving" through the agency.

OIVD Director Alberto Gutierrez recently projected that CDRH would release the draft guidance on companion diagnostics development in the first half of this year. A separate co-development guidance focusing on the simultaneous, multi-FDA center review of combination products will take much longer. By Gutierrez's estimates, that second co-developmpent guidance could be out next year or may take a few years to complete (PGx Reporter 12/08/2010).

Speaking at the Personalized Medicine Partnerships Conference this week hosted by Arrowhead Publishers, Mansfield noted that ahead of the official release of the companion diagnostics guidance, the statements she made regarding the regulation of such tests are "provisional" and may not reflect the agency's final stance on the issue. Nevertheless, she did offer some insight into the FDA's thinking that may be helpful to drug and diagnostic developers.

For example, she reiterated a previous recommendation that companies developing Rx/Dx combination products meet with FDA officials early in the development process to try to figure what the agency will expect from them, and noted that a growing number of companies have taken FDA up on its offer.

"We've really found ways to bend over backwards to move things forward," Mansfield said, adding that the FDA is also learning through its interactions with industry.

In addition, Mansfield shed some light on the agency's position on companion diagnostics that are associated with drug response or safety, which will likely require premarket approval, the highest regulatory requirement for a diagnostic. One of the reasons for requiring PMAs for these tests is so the FDA can track post-marketing adverse events associated with them, she said.

"We have stronger post-market controls with PMAs. You have to do annual reports, and you have to tell us if you change things and so on," Mansfield said. "It's really important if you design these tests to be able to tell who should get a drug … and we plan to keep a really close eye on these tests.

"So we will be doing more post-marketing stuff than usual," she added. "Certainly, we can do some of that with 510(k) [cleared tests], but PMAs really help us out here."

Although the agency requires that tests used to make treatment decisions for a specific drug receive FDA approval, it has determined that it will not refer to FDA-approved companion tests by brand name in drug labels, Mansfield said.

Anticipating that there might be multiple FDA-approved companion tests in the life cycle of a marketed drug, the agency made this decision so drug companies wouldn't need to issue an updated label every time a new test is approved for a drug. "If there is a compelling reason to name a test [by brand] in a drug's label, we will do that," Mansfield added. "But this seems simpler, and it accommodates new tests."

The FDA has already put this into practice. For example, during the time that Genentech's Herceptin was approved only as a treatment for HER2-positive breast cancer, the drug's label mentioned the FDA-approved HER2 tests by name and manufacturer. But when in October the FDA approved the drug as a treatment for gastric cancer, Herceptin's label noted only that "HER2 testing should be performed using FDA-approved tests by laboratories with demonstrated efficacy."

Furthermore, the drug's label now informs that breast cancer patients and gastric cancer patients may require different FDA-approved tests. "Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers," the label notes.

In cases where a companion test can identify patients at risk of an adverse reaction with a drug, then the labeling language in reference to the test may be stronger. "We have a literature and information scanning mechanism where we look for evidence that safety issues are arising once a drug is on the market," Mansfield said. If the FDA sees a safety issue with a marketed drug, then "we may ask you to relabel your therapy to include a test."

In this case, the FDA will likely require a companion test as a condition to keep the drug on the market. "If the test is required, then that means if you don't [have a companion test], then we may ask you to remove your drug from the market," Mansfield said.

FDA's evolving regulation with regard to genetic tests has often been criticized by some in industry as unclear, inconsistent, and detrimental to innovation.

"We didn't make up the concept of companion diagnostics. We're new to this, too," Mansfield said, addressing some of the criticism the agency has recently faced. "We're all about innovation. Half of what we see is new, but you guys … need to get real … Innovation is great, but it has to work. If you can't show me it works, I don't care if it's innovative."

Regarding one aspect of innovation in the industry — the rapid development of diagnostics based on whole-genome sequencing — FDA's critics have challenged that the agency is unprepared to address the regulation of tests on these platforms.

But Mansfield said the FDA has formed an inter-agency, inter-departmental working group to try to discuss some of its forthcoming challenges, including whole-genome sequencing technologies.

"We're as on top of it as we can be," Mansfield said. "Sanger sequencing, no problem. With the next-generation sequencing stuff … we haven't figured out how they will be validated entirely, but when they come through the door we'll have to figure it out."


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