NEW YORK (GenomeWeb) – 2015 was an active year for the US Food and Drug Administration, not just in the number of precision medicine approvals, but also on the regulatory front.
The agency held several workshops to gather public input on regulation of LDTs and NGS tests, and cleared the first genetic test for direct-to-consumer marketing.
However, throughout the year, pathologists and lab industry players continued to fight the agency's bid to regulate lab developed tests (LDTs). Many groups issued alternative proposals, one lab industry group hired lawyers to challenge the agency's statutory authority to regulate lab tests, and there was even a congressional hearing to discuss the matter.
Undoubtedly, the fracas over LDT regulation will continue into 2016. Alberto Gutierrez, director of the Office of In Vitro Diagnostics and Radiological Device Evaluation (OIVD) in FDA's Center for Devices and Radiological Health (CDRH), and Elizabeth Mansfield, deputy office director for personalized medicine within OIVD, reviewed with GenomeWeb areas of advancement and continued difficulty on the regulatory front last year, and highlighted topics the agency wants to focus on this year.
Below is an edited transcript of the interview.
You held a workshop in January [last year] to discuss FDA's LDT oversight proposal, and two workshops in 2015 to discuss regulation of NGS tests, the latest of which was in November. What did the agency learn from these meetings? And have these workshops helped the agency refine its regulatory thinking when it comes to LDTs and NGS tests?
Mansfield: It's somewhat important to separate the discussion in January on LDTs from the other ones on NGS. The workshops we held on oversight of next-generation sequencing tests are actually part of our Precision Medicine Initiative, where we are trying to develop a novel, more streamlined pathway for regulation of NGS, recognizing the differences in that technology and the way it's used, compared to traditional devices.
So, while there is an aspect of perhaps regulating LDTs there, that isn't what we were trying to address with those meetings. What we learned from those meetings was what a lot of people in the NGS community were thinking about — whether it was appropriate to implement compliance to standards and whether it was a good idea to have curated databases as sources of valid clinical evidence — to sort of streamline the ability to offer tests that have known analytical and clinical validity.
The LDT meeting was based on our draft guidance that was published the year before [in 2014], where we were discussing options and other items that were specifically related to oversight of LDTs. And what we learned from both [the LDT and NGS meetings] was that people are very opinionated about these issues. Especially on the LDT side, people gave us a lot of feedback that we were able to use, in addition to written comments, to help us revise the draft guidance in a way that was perhaps more thoughtful along the lines of how laboratories actually operate.
Focusing on the NGS discussions then, attendees of the November NGS meeting seemed to be saying, "We need standards." Is there anything concrete you can say about how you're thinking about regulating such tests, anything that you've solidified?
Mansfield: We haven't solidified anything, yet. Our intent is to publish draft guidances that will provide our thinking in a way that it evolves. Those [draft guidances] will be available for public comment. This is an area, like all other areas in regulation, we really want to get right. So, we will go through the draft guidance and final guidance processes.
Do you have a timeline for those?
Mansfield: Well, because this is the President's Precision Medicine Initiative, you can probably expect to see something while [Barack Obama] is still the president. Other than that I don't know that I can be much more specific. They will be draft guidances.
FDA issued a Class II designation with special controls in granting de novo 510(k) clearance for 23andMe's Bloom syndrome. Can you talk about how that came about? And what can industry players glean from this decision about FDA's approach to regulating direct-to-consumer (DTC) genetic tests and, if anything, about LDTs?
Mansfield: 23andMe submitted their Bloom syndrome test for our review and we determined through interaction with them and through our own research that this could appropriately be Class II when special controls were complied with. We developed those special controls, which are published and talk a lot about the types of studies you need to do and the information you need to make publicly available. It's sort of our standard de novo down-classification process, but it just happened to be a direct-to-consumer test.
What industry players can get from this is that we're willing to consider special controls as a way to get stuff to Class II, rather than being Class III. We have no implicit objection to direct-to-consumer testing, as long as it's accurate and reliable, and the people who receive the results can actually understand what they do and don't mean. 
Gutierrez: We were happy to look at areas where we can actually set special controls and apply controls more broadly than for just a test or several tests, when the risks are the same, when it's clear what you need to do and what you can claim.
FDA also used special controls in clearing Illumina's MiSeqDx platform. So, are special controls something FDA is open to using to lessen the regulatory burden on device manufacturers and test developers? Can you highlight some other areas where you might consider using special controls?
Mansfield: It's actually a statutory requirement.
Gutierrez: We've always been open to that but it's never been easy to find. To a certain extent the [NGS] field has matured some and there are areas where we can either work with [the National Institute of Standards and Technology] to find some material standards that would help us then define what you need to do to meet some analytical standards that happen within MiSeqDx, or where we can actually set performance criteria that we think are sufficient with special controls. So, we've always been open to this. Sometimes it's easier to find what those controls would be and which tests fit that, but it's not always possible. It depends somewhat on the test and what [test makers] are claiming.
Mansfield: But in general, we will always consider special controls with a new device that we previously haven't classified and whether [special controls] are sufficient to mitigate the risk so we can place the device in Class I or II.
A lot of this of course depends on test developers coming to the table, but at this time it seems that at least in the LDT realm not many firms have volunteered to take their tests through premarket review. Jeff Shuren, [director of CDRH,] at the November congressional hearing, appealed to the lab industry to "put down the swords." Are they? Can you highlight any areas of progress when it comes to LDT regulation?
Mansfield: The LDT stakeholders clearly, mostly still have some concerns about FDA oversight of LDTs. I don't think we can deny that. So, I don't know if that's what Jeff meant when he said, "Put down the swords."
We have not seen very many LDT developers rushing to get in before they have to, which we didn't really expect. On the other hand, we've made some significant progress in talking with different people in industry in explaining what oversight would actually mean for them and what the benefits are, and that they should be considering the benefits as well as the costs, which they're clearly concerned with.
Gutierrez: In general, even the laboratories have moved to a phase where there is some premarket review at least for whatever they consider high risk, particularly for those devices that perhaps use proprietary data and for which it is difficult to determine clinical validity with third party review.
Mansfield: Some people don't even want to acknowledge what we call LDTs are even tests. Yet, everybody now has at least proposed something to be done that's different than the status quo. So, clearly there's been an uptick in the conversation across the board.
So, a number of groups have come up with alternative proposals to FDA's oversight plan for LDTs. Have you reviewed these and would you consider incorporating any of the ideas in your own plan?
Mansfield: We're aware of all the ones that have been made public. So, of course we've looked at them. We've also met with these groups a number of times and talked to subsets of the groups, different laboratories and so on. If there are things that make sense to us within our regulatory structure we’re always happy to consider them but if they are essentially impossible to do under the current statutory framework, we couldn't do it right now.
FDA has issued a report highlighting 20 case studies where LDTs not regulated by the agency caused harm or could have. There has been some criticism of this report [from labs and pathologists], and one of them is that the examples in the report aren't based on peer-reviewed studies. What do you say to that?
Mansfield: First, it's important to note that these were case studies. This was not intended to single out particular tests that we don't like or to be the totality of the evidence that we have or anything like that. These were case studies designed to demonstrate the types of harms that could occur if an LDT were reporting incorrect results. The criticisms about peer review: We don't think peer review is actually designed to be the way that you would find a faulty test. It's kind of a long and involved [process].
Gutierrez: As a matter of fact, in some of the cases themselves, even though there was evidence [of harm] they could not be published because journals wouldn't accept it. Peer review is a difficult process for this kind of problem.
Mansfield: It's not the kind of thing that is often published and we actually do have a system, the Medical Device Reporting system, which can be used, that we would like to rely on rather than having people have to get through peer review to publish something in a journal.
So, a lot of the response to our case studies was perhaps [due to] misunderstanding how we operate and what we actually are able to say in public about what we know. We've received lots of information but if it's not publicly available, we're not going to go out and disparage a company without them being able to see the proof or evidence.
Another criticism of the report was that in many of the examples FDA oversight wouldn't have helped because healthcare providers used tests inappropriately, and of course, FDA doesn't regulate the practice of medicine. Other critics have said that FDA approved tests aren't perfect either and have flaws. Can you also respond to these critiques?
Mansfield: We agree that FDA-cleared and approved tests aren't perfect either. However, what we do have in the cases where people bring in something that isn't perfect, which is every test, is labeling that tells you how the test is performed, and provides limitations and warnings about what the test can't do or things that you should be worried about. We don't know for sure because the study hasn't been done, but people misusing the test could have been easily averted by appropriate labeling, which we would require under our oversight. While anybody can misuse any test at any time [and] we don't regulate the practice of medicine, we would like for people to have the correct and accurate information in their hands upon which to make a decision.
Also, this past year there were a number of reports highlighting questionable ethical practices of genetic testing companies, where firms allegedly paid doctors for ordering their tests. This has raised questions about whether there need to be more stringent rules about conflicts of interest and requirements for disclosures in the diagnostics industry. Is this something the FDA is looking into or can do some work in?
Mansfield: I'm not aware that this is an area where FDA would have authority.
Gutierrez: The one place we're looking into a little bit is models in DTC that rely on ordering of the test either by the physician that is incorporated into the company or that somehow has a relationship not with the patient but with the company. That's an area we're looking at. But the other [aspects], we at this point are not [looking at].
Mansfield: We're not looking at that, but another agency might be.
This year, the FDA is planning to hold more workshops and maybe issue more guidances. The agency has highlighted that the codevelopment guidance would be coming soon, for example. What can we look forward to this year?
Mansfield: I realize we've been promising that guidance for quite a while now. As with all guidances, it's very hard to predict when something is actually going to get out, but I do believe that [the codevelopment guidance] will be published early this year. We've made a lot of progress and we think we're almost there on that.
We'll also be having some additional public meetings. One of them will be for patients and providers around next-generation sequencing, and the types of results patients would like to get and what providers want and how they would use [the results]. It won't be the meeting that establishes how we do anything, but we do need to hear from the people who will be getting these results.
We also intend to hold a meeting, and the notice will be published very shortly, about next-generation sequencing onco-panels, which are actually in use as LDTs right now. There is a lot of interest from the traditional in vitro diagnostics industry in getting some of these cleared or approved. And then the LDT guidances are on the "A" list [for guidance development] and a number of other center-specific guidances.
The FDA has said publicly that it plans to finalize the LDT guidances this year, but if the agency does so, there is reason to believe that some in the lab industry might sue. Is the FDA prepared for that?
Mansfield: Uh huh. We would like to finalize the guidances. Clearly, people are entitled to sue us. But the whole question in a lawsuit is if there is any basis for it. We're aware of our risks, but we think it's the right thing to do from a public health standpoint. And so, that's what we're trying to do.