Toward the end of 2013, the US Food and Drug Administration surprised many by taking action on a number of divisive and complex areas in the personalized medicine space.
In November, the FDA granted 510(k) clearance for Illumina's MiSeqDx, the first sequencing platform to receive the agency's nod. Simultaneously, the FDA cleared two cystic fibrosis assays that run on the MiSeqDx and a reagents kit that allows clinical labs to develop their own tests using the platform.
A few days later, the agency finalized a controversial guidance advising manufacturers how to properly label and market in vitro diagnostic products for research- and investigational-use only. In the final version, the FDA clarified language that manufacturers previously felt placed an undue burden on them to regulate the appropriate use of such products. While the wording in the new guidance may be more delicately put, the thrust of FDA's main concern remains the same with these products – that IVDs intended for research and investigational use should not be sold and marketed for medical use.
Also around this time, the FDA sent a warning letter to direct-to-consumer genetic testing firm 23andMe, signed by Alberto Gutierrez, director of FDA's Office of In Vitro Diagnostics and Radiological Health, that asked the company to "immediately discontinue marketing" its Personal Genome Service "until such time as it receives FDA marketing authorization for the device." The letter revealed that despite the long-standing interactions between the agency and 23andMe, the company had failed to meet the FDA's evidentiary requirements proving its tests are safe and effective for broad public use. Following the letter, 23andMe stopped marketing health-related genetic tests to new customers.
With these three actions, the FDA had to grapple with issues that are critical to the advancement of the rapidly evolving personalized medicine field. The agency asserted in the RUO/IUO guidance that tests intended for research are not held to the same regulatory standards as tests intended as part of patient care. This stands to significantly impact the way test manufacturers and labs conduct their business.
Since it's widely believed that next-generation sequencing-based diagnostics will be more readily used in mainstream patient care in the near future, by clearing Illumina's platform, the agency carved out a clearer regulatory framework for other NGS tests providers to follow. And lastly, with the continuing surge in genomic advancements, it's inevitable that consumers will become more interested in their DNA data and will want to use this information to make medical decisions. By taking action against 23andMe, the FDA maintained consumers' access to their raw DNA information, but held industry accountable for proving that their interpretation of what the data means for people's health is based on sound science.
Gutierrez and another top official from FDA's Center for Devices and Radiological Health – Elizabeth Mansfield, director of personalized medicine – discussed the agency's efforts in the personalized medicine space in 2013 with PGx Reporter. Below is an edited transcript of the interview.
At the end of the year, you finalized the RUO/IUO guidance. Are there any changes or new ideas in the guidance that manufacturers should be aware of?
Mansfield: We did modify the language a little bit between the draft version and the final version. We did take out, as everybody noticed, the … language that people had read as putting the responsibility on manufacturers to know what their clients were doing with the [RUO/IUO] products. We did back off on that a little, but that doesn't really mean anything. Manufacturers are still responsible for putting the correct label on their devices, according to their intent for their device. So, I think we did revise the language, but it doesn't really have a substantial difference in outcome in the end.
In reporting on the field, it seems to me that the use of RUO/IUO products is widespread, particularly when it comes to next-generation sequencing-based tests. In tracking the appropriate use of RUO/IUO products, will you depend on industry to self regulate or do you plan to increase oversight in this area?
Mansfield: Certainly, by putting out the guidance, we had hoped to help [manufacturers] regulate themselves. It's still their decision about what they want to do with their products, and their responsibility to label [them] according to that [guidance]. The guidance should help them in making decisions like that. We have for a long time been contacting companies and telling them, 'We don't think your product is labeled properly and you need to do something about it.' That often gets the appropriate results. If that doesn't work and we still think there's a problem, then we can resort to further compliance actions if we think we need to. I think we'll still be following the same compliance pathway we always have. We're just hoping that the guidance will help manufacturers make better choices for themselves.
I did note that in the final guidance there were, for the benefit of industry players, some examples of instances when the agency might take action against a manufacturer for inappropriate marketing of RUO/IUO tests; for example, if a manufacturer is selling RUO products to a lab that doesn't conduct any research. Are these examples drawn from real life? Have you noted that type of activity?
Mansfield: I think that's just sort of a common sense correlation. If you're selling a lot of products labeled research-use only to a lab that doesn't do any research, that would certainly seem a little unusual. You would want to consider how you would justify that if somebody came knocking at your door.
Gutierrez: There are a couple of other areas where, if you look around you, there are practices that are clearly over the edge. All you have to do is an RUO search on the web and you'll find lots of devices that are labeled RUO and yet they're making medical claims. So, we are hoping that this [guidance] will help [manufacturers] understand what kinds of claims they can make, and to actually market their devices appropriately.
I was hoping you could also discuss your recent clearance of Illumina's MiSeq platform, the reagents kit, and the cystic fibrosis tests. I recently saw a picture of a diagnostic company's premarket approval submission to the agency for a [non-NGS based] test. There were binders as thick as telephone books piled high and filled an entire table. What did Illumina's submissions to garner the MiSeq clearances look like? Can you talk a bit about the kinds of resources the agency put behind reviewing these submissions so quickly?
Mansfield: We were fortunate that the company submitted 510(k)s, which tend to be somewhat smaller volume-wise than PMAs, but no, it didn't cover a whole table. But we had been preparing ahead of time, for a couple of years in fact, talking to manufacturers and labs and other users about sequencers and formulating the kinds of questions we would want to ask about them to get at their performance. We had invited all of them in to the FDA to give us seminars and to do question-and-answer sessions. So, we had a pretty good idea of where we were going when Illumina came in. And Illumina actually did a pretty good job of providing us most of what we wanted right up front. So, we were prepared on the scientific side and Illumina was prepared on their side as the manufacturer, and had gotten their quality systems under control. It was actually not terrifically difficult. We were able to ask the questions we thought we needed to and Illumina was able to answer them.
It's interesting that people often think that FDA will have a lot of trouble with new technologies. Really, when you get down to it, most in vitro diagnostics will have similar questions about performance. You just have to tailor them to the particular type of device.
Gutierrez: And some of the harder questions are really the policy questions and the regulatory questions. In this case, we were up front in trying to figure out what really made sense and how [we could] proceed in a way that both provided enough regulatory control for us to have some confidence in the technology and at the same time, not fight those battles that were not worth fighting because there is nothing you can do about certain things.
Mansfield: As you'll see, [from the approval letter] … the special controls we've put in place rely a great deal on the labeling of the device, and that was the most critical parameter. It's not that the device worked perfectly in every situation; but does the user understand how it works in different areas of the genome, so they can know what they had? From a policy point of view, [that] allowed us to move that submission through pretty easily. We weren't insisting on perfection. We were just simply insisting on truth.
Based on what you described, it seems the regulatory process for Illumina's NGS platform and CF tests went pretty smoothly. But did anything happen during the review process that the agency didn't anticipate?
Mansfield: You know, I can't really think of anything. We had already thought about it a great deal. We worked a lot on it. It just went smoothly. One of the things in the cystic fibrosis area that we were able to do for those particular applications was [to use] Johns Hopkins' CFTR2 database. They've done a very good job of putting together a curated database [of gene mutations] that had levels of evidence behind it. We were able to refer to that database to clear a test with many more mutations than we had ever been comfortable doing before. I think we did 139 in this one. And it was because that particular database existed and we were able to verify it and so on. So, that was new and really showed how the collection of evidence in a well-curated way can really help on the regulatory front. The company didn't have to go out and generate all that information. It was already there.
After these clearances [which took around a year], does the FDA now have a framework in place to bring other NGS-based tests through this process in such a speedy timeframe?
Mansfield: We made … the platforms themselves Class II exempt. That means if other tests have essentially the same intended use as the one we cleared, then they don't even have to make a submission. They just have to make sure that they do all the things that are in the special controls. That's about as generous as a regulatory pathway as you can imagine. And the reagents as well are Class I exempt. That's a very light touch.
I know FDA doesn't talk about ongoing reviews, but are you looking at other NGS-based platforms?
Mansfield: Yeah, we can't talk about it. But you know, there is a lot of interest in all kinds of applications out there using next-generation sequencing. And I don't think anybody will be surprised to see new applications coming along.
Gutierrez: Right. New intended uses would require [test developers] to come in [for regulatory clearance or approval.]
Mansfield: There's probably a lot [of] interest in particular assays, not just the open platform, but already established assays.
The clearance of the MiSeq platform offers labs and researchers a chance to use an FDA-approved product instead of an RUO/IUO product. We've heard that some CLIA labs using the RUO version of MiSeq do not plan to switch to the FDA-cleared kit since it will likely be more expensive and, because of the locked-down specs, labs won't be able to make changes to the platform as needed. Do you think FDA clearance is enough to spur customers to make the switch from using an RUO platform to a cleared kit?
Mansfield: It's hard to say. Having been in industry, I understand the tension with cost. So, I don't really know. I hope that the availability of an FDA-cleared sequencer would attract people. It certainly should be easier if you're starting up a next-gen lab now to have something you know was manufactured in a controlled manner and has specific performance characteristics. But we really wouldn't have any way to predict what a lab would or wouldn't do.
Moving on to FDA's warning letter to 23andMe, a lot has been written in favor of and against FDA's action against the DTC genetic testing firm. Those who are against FDA's move have characterized the agency as paternalistic and have accused the FDA of hindering the public from accessing their own genomic information. In fact, the agency has not restricted consumers' access to their raw genomic data without interpretation. Where does the FDA stand on this genome data access issue?
Mansfield: I think we have said publicly several times that we have no problem with people having access to their raw genomic data. As soon as a third party starts to interpret that and tell you that it has health implications, it gets to be a medical device. Depending on what type of information they're giving back, that may be high-risk, moderate-risk, or low-risk information. So, I think that's where we are. If you want to get your DNA sequenced, go ahead. But if somebody wants to interpret it in terms of your health, then we think that we probably need to be involved.
Gutierrez: We don't have an issue with people getting their own [genomic] information or with companies providing that information, as long as they have come through the agency and shown that the device is safe and effective, and are labeled correctly. Clearly, we would encourage them to do so and then to provide the information they have to people.
The FDA hasn't regulated genomic data interpretation programs like Promethease, to which people can upload their raw data and learn their risk for diseases. Why are or aren't these types of interpretation programs in FDA's regulatory purview?
Mansfield: I don't know that particular one, but I do think we consider these to be medical devices. We are working on a framework that talks about these types of devices and what kinds of controls need to apply to them. So, I do think they're devices.
At the start of 2013, we talked about a host of the things you wanted to get done throughout the year. Is there anything that you wanted to get done last year that you didn't get done?
Mansfield: I think we did an incredible amount in 2013, not just in personalized medicine, but in IVDs altogether. We're very proud of what we got done. I think there were a couple of guidances that we would have liked to get out sooner. We've been working around the new technologies, and we see the other ones coming down the pike that we're getting ready for. But 2013 was a good year for us.
Any hints about what we can expect from FDA in 2014?
Mansfield: We have products that we think are interesting and novel that we hope to clear or approve. We have a stable of guidances that are all waiting to be turned loose on the public, including a couple of personalized medicine ones. The [drug/diagnostic] co-development guidance it seems like we've been talking about forever. We're going to get that out this year, I'm pretty sure.