NEW YORK (GenomeWeb) – 2016 was a busy year for the US Food and Drug Administration in the personalized medicine space.
The agency approved a slew of new drugs with companion and complementary diagnostics but also demonstrated flexibility in its regulatory policies (see related story and chart). Also, the FDA held several workshops last year to garner feedback from labs, diagnostics developers, physicians, and patients, and issued draft guidances on the regulation of next-generation sequencing tests based on their comments.
But the FDA action that gained the most attention last year was the agency's announcement that it would hold off finalizing regulatory guidance for laboratory-developed tests. Alberto Gutierrez, director of the Office of In Vitro Diagnostics within FDA's Center for Devices and Radiological Health, and Elizabeth Mansfield, director of personalized medicine and molecular genetics within OIVD, recently discussed their efforts in this space over the past year.
Below is an edited transcript of the interview.
One of the biggest events in the diagnostics space last year was FDA's announcement to hold off on finalizing the LDT guidance. A lot of people have wondered whether the agency still maintains that it has authority to regulate LDTs. If so, how do you plan to extend enforcement?
Gutierrez: If you look at the draft guidances, when we issued them, we actually issued a response to several [Citizen] Petitions that dealt with whether the FDA had jurisdiction or not. That was the agency's legal opinion and we still hold that legal opinion. So, yes, we do believe that we have the jurisdiction to regulate LDTs.
Right now, though, as we have said, we are holding off to see what all the parties are putting on the table. And we're having a discussion on how we can move forward. To a certain extent with a new administration, clearly, we are also waiting for guidance on how they would like to proceed. [Editor's note: see below for pdf of FDA's Citizen Petition denial to Washington Legal Foundation.]
You issued a report in 2015, outlining some instances where the agency thought that LDTs were harming the public health. In areas where you suspect there is a public health issue, are you still going to act on those situations with enforcement?
Gutierrez: We don't believe there will be a change in that. If we do see a public health risk, we will do something to try to mitigate that risk.
Last year, there was a lot of activity in the area of NGS tests. The FDA issued draft guidelines on the regulation of NGS tests, launched PrecisionFDA as a way to advance NGS bioinformatics resources, and made permanent the Parallel Review pathway. The device center has said that one of its goals in 2017 is to finalize the NGS guidances. Do you think test developers will still voluntarily partake in these regulatory initiatives that you've put together regardless of what happens with LDT regulation?
Mansfield: We certainly hope so. What we've put out there was essentially a function of good science and good current practice. So, we hope that even if people don't come into us, that we start to develop standards in this area, so everyone can start to understand what the best practices are and follow them. And then, if they want to come into us, they'll be in a great position. Clearly, for LDTs where — well you know where we are on LDTs — but for other entities that want to provide tests the conventional way, we suspect they'll be very interested in this pathway.
You held several public workshops on NGS tests in the past year. Can you talk about some lessons learned that informed your work and how your feedback may have helped the companies you're interacting with?
Mansfield: We have heard from companies we're interacting with. They've read the guidances, and given generally very positive feedback. We heard a lot of great feedback through the workshops. A number of those happened before the draft guidances were published, and so part of that [feedback] was incorporated into the guidances. We continue to [interact], not necessarily through workshops, but on a one-on-one basis, with different players, whether they be professional societies, standards bodies, or individual laboratories. Our goal is to continue to be active, to learn in this space, and get stakeholder feedback.
And of course we want to finalize the guidances. So, all of the feedback we get before we finalize the guidances should be incorporated. Because of the way we've set things up, as being standards-based, [we have] flexibility for new information to be taken in and dealt with, without needing a lot of new guidances.
We really think the way we've set it up can drive innovation in ways that are possible for conventional manufacturers, as well as laboratories, to deal with. We're not asking for things that are completely unfamiliar to anyone. But we're setting boundaries around what we think best practices are.
There was one particular workshop where FDA invited physicians and patients to weigh in on aspects of NGS testing. Do you think those communities have more to contribute in terms of NGS testing, and are you planning on involving them in other areas going forward?
Mansfield: We do intend to engage all stakeholders at all levels as we move forward. As you know, CDRH and FDA in general, have taken a much more patient-focused [approach], held more listening sessions, trying to understand from patients and physicians what it is they want, what their risk tolerance might be, and so on. So, in terms of our analytical and clinical oversight, and mechanical processes, I don't think that specifically changes, but how we think about risk and how we think about results being delivered can very much be affected by input from physicians and patients. That's really important to us as we move forward, that we assess risk in the same way as society thinks about it, and not be off in our own corner thinking about it differently than the people who are actually being affected by the tests.
The last personalized drug and companion diagnostic FDA approved in 2016 was Clovis' Rubraca and Foundation Medicine's FoundationFocus CDxBRCA. That's the first FDA-approved NGS test. The approval process was very quick, and Foundation has said in a press release that the CDx approval is an advance toward getting a universal CDx approved. Can you talk about your experience approving the BRCA test?
Mansfield: Foundation came in reasonably prepared. I think it did set a basis for others to look at and see what was required in terms of companion diagnostics. How that translates to a universal companion diagnostic is not exactly clear yet. There are new questions that are raised when you're looking at multiple different analytes that have multiple different actions associated with them.
What that approval did demonstrate is that when FDA is presented with relatively new technology, the agency can act responsibly and can get approvals out there that are useful for patients. Stakeholders should not fear [FDA review] as something that will be an unachievable hurdle for them.
Some stakeholders have pointed out the strengths and weaknesses of that NGS companion test, which are in the FDA-approved labeling. They've noted that there are other tests on the market, one approved by the FDA and most not, that are better than what Foundation has gotten through the agency. Which brings up this whole issue of whether there is a benefit to getting FDA approval when there may already be other, better tests out there. But isn't the whole point of FDA approval to inform the public of the strengths and weaknesses of a product?
Mansfield: That has a great deal to do with it. It's very clear what the test does and doesn't do. There may be better tests out there, but we're not doing comparisons, [asking] if this test is better than that test. And we're not claiming by approving this test that this is the best test in the world.
Gutierrez: And nobody knows, because that data hasn't been independently evaluated and they're not necessarily transparent.
Mansfield: [Foundation] had clinical outcome data and so on, so we have a lot of confidence in how that test performs, because it's actually tied to clinical outcome with this particular drug. So, what does it mean? Should people come in to get FDA approval? I think, if you want independent third party review, if you want clarity about how well your test performs, this is one way to do it. I don't know if it would be speculation to say this will affect payment or not. I have no idea. We don't make those decisions. But it's certainly a way to put a stake in the ground. We do understand how this test performs and you can count on that.
Complementary diagnostics is another category where FDA approved more tests last year, in the context of anti-PD-1 and -PD-L1 drugs. There has been a mixed reaction to this category because doctors seem confused by when and whether to test patients and which test to use. Does the FDA expect to continue to approve complementary diagnostics to advance precision medicine, and in what circumstances is this category likely to be most useful?
Mansfield: Complementary diagnostics are not a requirement. We hope it's useful in the precision medicine arena because it adds information. No one is required to come in with a test but it adds information that's useful to physicians and patients in making decisions. I've heard from people [using such tests] that it's been very helpful for them to determine with the patient what strategy they want to take. That's going to be part of what precision medicine does, actually give you more information so you can make more informed decisions. We hope this model is part of our armamentarium, but we're not requiring anyone to come in with a complementary test.
Gutierrez: We think this is the right thing for patients. In reality, complementary diagnostics is something we've had in one way or another with other diagnostics. That is, a drug goes out and eventually you do some kind of drug monitoring and you're able to make better decisions on dosing based on the test. When those two things, [the drug and the test,] don't match up and come at the same time, it makes it difficult for physicians to know what tools they have to treat the patient correctly. So, complementary diagnostics, if they come at the same time [as the drug,] should be very helpful for the doctors, because they'll have better tools to treat their patients.
CDRH published a priority list of guidances it wants to get out in 2017. Is there anything else we should look out for this year?
Gutierrez: Our priorities are finalizing the two NGS guidances, and the CLIA waiver draft guidance. Essentially those are the things we're working on at this point. Anything else that comes up will be based on submissions that come in.
Mansfield: We have a couple of other policy guidances that may come out this year, but we can't promise anything. We have a lot of work here to do, and priorities come first.