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In Surprise Draft Guidance, FDA Suggests It Should Oversee Multivariate Index Assays

The US Food and Drug Administration last week issued an unscheduled draft guidance that seeks to encourage molecular diagnostic companies to file for pre- and post-market review tests that use an algorithm to generate results from multiple data points, rather than following traditional homebrew rules.
Unlike many other FDA guidance documents, the Center for Devices and Radiological Health’s document does not delve into scientific issues but instead explains the agency’s view of its regulatory role concerning these kinds of tests.
The agency composed the draft following recent meetings with Genomic Health, whose Oncotype Dx test uses a gene expression profile to calculate the likelihood of breast cancer recurrence.
The document, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Assays, is meant to help answer the murky question of who oversees this fairly new category of devices, and the agency specifically appears to be trying to prevent another company from taking the same regulatory route as Genomic Health took with its Oncotype Dx test. The firm began selling the test, which is performed in its own CLIA-approved lab, without seeking regulatory approval.
In the draft, the FDA said it has had jurisdiction over IVDMIAs but that it has chosen not to exercise it because it hasn’t yet examined the issue closely. Now that it has, the agency asserts that IVDMIAs “include elements … that are not among these primary ingredients of in-house tests and that, therefore, raise safety and effectiveness concerns,” according to the draft guidance. The document can be seen here.
“I think when people are given the impression that what they have developed is not a regulated medical device — and this document is clarifying that — they will be changing the way they are talking to us,” Courtney Harper, associate director for toxicology at CDRH’s Office of In Vitro Devices, told Pharmacogenomics Reporter this week. Harper coordinated the draft document’s composition and wrote portions of it.
The draft guidance states that IVDMIAs meet three criteria: they use clinical data; they use an algorithm to calculate a patient-specific result; and they report this result in such a way that a well-trained clinician cannot interpret it without prior knowledge of the test.
Some companies whose diagnostics are already cleared won’t be affected by the FDA’s new approach, said Harper. However, for devices qualifying as IVDMIAs that are currently marketed by CLIA laboratories, “the guidance basically specifies that, in a risk-based manner, they should be regulated in some fashion,” she said.
According to the document, the FDA will regulate IVDMIAs based on their risk level. Low-risk Class I devices will generally be exempt from premarket review while higher-risk Class II and Class III devices will typically require a 510(k) premarket notification and an application for premarket approval, respectively. Most IVDMIAs will likely be Class II or Class III, OIVD said in the draft.
The draft also states that IVDMIAs are subject to Quality System Regulation and Medical Device Reporting regulation. The FDA intends to issue a guidance to help laboratories comply with these two provisions.
In general, the document “would certainly apply to most” diagnostics that measure multiple gene expression profiles, genomic SNPs, or proteomic variables, and then process the information into a clinical answer using an algorithm, Harper said.
While many of these devices use high-throughput technologies, the guidance also applies to simpler technologies and algorithms that take into account other types of data, such as demographic information, she said.
Some end-user laboratories may also be affected by the FDA’s new approach even though such labs may not consider themselves diagnostic companies. “If they manufacture these devices, then they are in effect manufacturers,” said Harper.
Setting the Stage
Genomic Health markets its multivariate, algorithm-based Oncotype Dx nationwide and performs the test in its own lab under CLIA rules. On Jan. 23, OIVD send the company a letter stating that the FDA had no record of a pre-market review of the test.
It asked Genomic Health to set up a meeting with OIVD ”to discuss the nature and appropriate regulatory status of your technology, and the least burdensome ways that Genomic Health may fulfill any premarket review requirements that may apply."
In its letter, the FDA said it considers the test a device under section 201(h) of the Federal Food, Drug, and Cosmetic Act. The current draft guidance defines IVDMIAs as devices under this section of the FDCA.

“I think when people are given the impression that what they have developed is not a regulated medical device — and this document is clarifying that — they will be changing the way they are talking to us.”

Asked specifically whether Genomic Health or another company with a CLIA-approved lab that markets an IVDMIA diagnostic would have to seek FDA clearance, Harper said: “I will acknowledge that some companies have business plans that are not along [FDA’s regulatory] lines, but can’t comment on what their business plan is or what moves they will make.”
Genomic Health co-founder Patrick Terry said the company is “still in dialogue with the FDA over this whole space of these types of technologies” and plans to “work with the FDA in thinking through this process.”
“Obviously guidances and draft guidances don’t have the effect of law or regulations, so there’s no immediate impact,” Terry said. However, he said the company is pleased that the FDA is clarifying which areas it feels are suited to oversight.
Asked about comments that the draft has generated so far, OIVD’s Harper said the agency has “certainly gotten a few questions, and I’m imagining that we’re going to get quite a few comments for the docket, but I haven’t seen any of those yet.”
At this point “people are mainly at this point asking for clarification … so I think that people are probably digesting the document,” she said. Harper declined to say what other kinds of comments her office had received because she said she had not seen all of them.
Terry said Genomic Health was preparing its comment through trade associations. He said he would not characterize the draft guidance as a positive or negative development, instead painting it as a “balancing act” of regulatory burden and technology development.
The FDA has never exercised regulatory authority over the IVDMIA category of devices, and “the community – broadly – is engaged in getting its arms around this,” Terry said. “Something the community’s struggling with is, ‘Well, how do you put this into context?’ Nothing like this has ever been released before, so the community is still getting a sense that this is all a surprise,” he said.
Harper said she did not know whether comments would be made publicly available, nor how many comments FDA has received so far. Comments on the IVDMIA draft guidance can be submitted to OIVD here. The comment period closes December 11.
After OIVD reviews, comments on, and revises the IVDMIA draft guidance, the FDA should issue a final guidance in “a short time period,” although estimating its publication date is difficult, Harper said.

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