Illumina’s Gregory Heath envisions rapid growth for next-generation sequencing in clinical applications
Interview by Steve Halasey
Last November, FDA granted market clearance to the first next-generation sequencer to be cleared for diagnostic applications, the MiSeqDx sequencer by Illumina. The clearance was accompanied by a number of blogs and editorials by healthcare topsiders, celebrating the potential of NGS systems for improving patient care. To get the inside scoop on Illumina’s expectations for the system, CLP spoke with Gregory F. Heath, PhD, the company’s senior vice president and general manager for diagnostics.
TECHNOLOGY DEVELOPMENT
CLP: Sequencing technologies have advanced gradually but steadily over the past decade, in the process becoming both faster and less expensive. What were the key technological challenges that needed to be overcome to arrive at the stage represented by the MiSeqDx system?
Gregory Heath: In general, most of the technical hurdles were around imaging and being able to image more data faster. With regard to MiSeqDx specifically, we had to build some ease-of-use features into the system. When next-gen sequencing was first made available, it required fairly sophisticated users and lots of bioinformatics; we’ve tried to incorporate more of the workflow and more of the data analysis into the box, to make it more user-friendly. Those are the things that really culminated in the MiSeqDx system.
CLP: Were there any steps that created particular delays or threatened to derail your development?
Heath: Not really. The core technology—Illumina’s sequencing by synthesis (SBS) chemistry—is very robust, and there’s still a lot of headroom to improve costs, speed, and turnaround time. We were confident that there weren’t a lot of technical risks left when we were developing the product.
OUT OF THE (RESEARCH) LAB
CLP: NGS sequencers have a natural home in research labs, but the Illumina system is the first approved as a diagnostic analyzer. Was it tough to make the decision to assign resources to the development of an FDA-cleared diagnostic system?
Heath: The short answer is no. Sequencing is a fundamental technology that will be used pervasively across a number of different applications. We have been very successful in the research space, and diagnostics was the next biggest market. So it was easy for us to ask, ‘If we want to continue to grow and expand, what’s the next adjacent area for us?’ And that was diagnostics.
CLP: What technological and market factors went into that decision?
Heath: We looked at four particular applications where we believe sequencing will play a significant role over the short term. First, genetic disease, particularly around reproductive genetics. Second, oncology, where the performance characteristics of the product match uniquely to some of the challenges—particularly around the heterogeneity of tumors, and the need to sequence deeply in order to identify minor clonal populations that may have driver mutations. Third, infectious disease, particularly around microbiology and viral infections; the technology still needs to be a little bit faster to handle extreme cases such as sepsis and meningitis, but we’ve made great strides and continue to move in that direction. And finally, transplantation and transfusion medicine, looking at things like tissue typing; many of the past technical challenges around being able to do long reads for HLA, so that you can do tissue typing, have now been overcome. Beyond those four diagnostic areas, there are several others—such as forensics and food safety—where NGS technology is already starting to play a role.
CLP: What new resources did you need to develop or contract in order to address regulatory requirements?
Heath: There was a lot of fundamental skill-building throughout the company, but the expertise we really needed to add was in regulatory and clinical affairs. We built a regulatory group, since we definitely needed to have some expertise in that space. We built a clinical affairs group that we definitely needed to do our clinical trials work. We enhanced our quality team to make sure we could meet ISO and GMP requirements. We also reinforced our development team with a number of folks who came out of the diagnostics industry and had experience with FDA submissions—people who had worked in a regulated space before.
CLP: It is a significant commitment of resources to hire so many people who have experience with FDA-cleared devices. Is it those sorts of requirements that are keeping companies out of the NGS space?
Heath: I think those elements are necessary, but not sufficient. One of Illumina’s major advantages is a large presence in the research community—because everything starts in research. From there, we could see the direction that translational medicine and clinical science was moving, making its way into the clinic. By having that vantage point, we were able to anticipate which areas were likely to emerge and be true innovations.
Illumina’s core technology is also an essential ingredient. There are few companies, even in the life sciences space, that have a technology so fundamental and pervasive that it can be leveraged across a number of different applications. That’s one of our big advantages.
Another thing is that Illumina is a very collaborative company. We work a lot with our customers, and we work very well within the company. We have folks all in one group who design the instrumentation, the chemistry, the software; that enables us to move pretty quickly and nimbly to address those opportunities.
CLP: What were your assumptions about third-party reimbursement for the tests that are running on the MiSeqDx system, and how did they contribute to your thinking about how quickly to move into the clinical diagnostics phase?
Heath: In the developed world—Western Europe, the United States, Japan—the key healthcare challenges are going to be around heart disease and cancer primarily. And with an aging population, you also have some cognitive neuroscience diseases that are going to really put some strain on healthcare costs. Our approach is to try to deliver more value for the money.
Under the old reimbursement coding system, someone once told me, if you used code stacking to file for a whole-genome sequence, the reimbursement rate would amount to something like $3 billion. Well obviously, that level of payment is not going to happen. But we’re delivering that information at a much lower price point. In the current paradigm, we’re delivering a lot more value for the money, and we think that by doing so, the technology will be accepted more broadly.
But we don’t think NGS should be reimbursed just at a technology level. For example, if you sequence E. coli in somebody’s gut microbiome, that context has a certain value to it. But if you sequence E. coli in the bloodstream of a septic patient, that context suggests a very different value—because if that patient isn’t treated, he could be dead in a day.
So we think that value is dependent on context, but we also think we can deliver a lot more value for the money. That was our ingoing approach. Specifically for the CF assays, reimbursement is set at reasonable levels for both the screening and the diagnostic assay where we’re giving a lot more information. We think we’re delivering value for the money, and reimbursement shouldn’t be an issue for us.
CLP: What is the CLIA status of the system? Do you expect this will change over time?
Heath: The screening assay and the diagnostic CF assay are both high complexity tests, but that will definitely change over time. The sequencer itself is fairly streamlined: once you put your sample onto the instrument, it’s pretty much hands-free from that point on. You can walk away and go to your computer and analyze the data as it downloads. But the upfront sample prep can vary a lot depending on the specific application. We’ve been working on making both the front-end and back-end simpler through some acquisitions, and also internal development. We’re trying to streamline some of the sample prep components as well as the interpretation components. That’s where we enter into more complexity, I think.
RESHAPING THE MARKET
CLP: Illumina launched MiSeqDx with a menu of just two tests, for cystic fibrosis, but also received approval of the reagents necessary for labs to develop their own tests. Does Illumina plan to build a menu of additional tests?
Heath: Yes, definitely. We’ll be working in essentially the four areas that I mentioned, with particular emphasis on genetic disease and oncology. We think those two will be the next growth areas. Genetic disease is the basic bread and butter of next-generation sequencing, since that’s the area that the technology grew out of. We’re going to continue to push through that space. Oncology is very broad, so we’ll likely work in conjunction with a number of partners. There’s a high level of interest in oncology from pharmaceutical manufacturers, because it is such a challenging problem, and we think we’ve got the perfect technology to address some of those concerns.
CLP: Would the resulting products be regulated as companion diagnostics, and marketed together with a drug component?
Heath: Yes, in some cases they will be companion diagnostics. And in other cases, they’ll be stand-alone tests.
CLP: How will the availability of the MiSeqDx change laboratory creation of LDTs?
Heath: We think it will accelerate some lab-developed tests, because now the instrument is cleared. For the staff who have to validate their laboratory’s workflow from raw sample all the way to results, a large component of variability has now been removed. With a cleared instrument, the lab can now focus on assay development, knowing that the instrument has stood up to FDA’s rigorous review. So, we think it will make life a lot easier for people wanting to create LDTs on the platform.
CLP: Will approval of a standardized platform also make it easier for labs to seek regulatory approval for their LDTs—and for FDA to grant it?
Heath: I think so. It’s a component of the system that’s already been through the clearance process, so now the lab can really focus on the performance of the assay and the interpretive software. To the extent that labs continue to build on the same platform, we should see prompt lab comparability and a higher degree of standardization. All of that also helps.
CLP: Do you believe that existing clinical labs will be the major market for MiSeqDx? What other settings do you expect to provide sales growth—e.g., near-patient hospital settings, outpatient and ambulatory centers, long-term care facilities, physician offices?
Heath: In the long run, it’s possible to enter all of those markets. A lot of this will be driven, of course, by the specific clinical application. In oncology testing, of course, people always want answers as quickly as possible. But for someone who has undergone surgery and is going to start chemotherapy in four to six weeks, there is time for tests to be performed in a central lab. Since most cancer patients are treated in community hospitals, we might see testing migrate into the community hospital setting.
On the other hand, if you’re talking about something like a test for sepsis, then you might find testing moving into the intensive care unit.
Long-term care facilities are less likely settings, because many of the problems there tend to be more chronic than acute. But it’s possible that NGS testing could move to more of a point-of-care application if you were trying to identify something like a resistant strain of bacterial infection or meningitis.
A PERSONALIZED FUTURE
CLP: How do you see the evolution of personalized medicine proceeding, now that an NGS system is available?
Heath: I think things will get more personal, if I could put it that way. People who have their whole genome sequenced all of a sudden make a lot more information about their particular circumstances available to the treating physician. Even a person with no medical conditions, once sequenced, could make their pharmacogenetic information available to the treating physician or pharmacist. For example, about 7% of the U.S. population has a mutation in cytochrome p450 that prevents them from benefiting from certain drugs. In order to metabolize codeine, for example, the individual has to possess wild-type genes, so that the codeine can be converted to an active state; otherwise, the patient would derive no benefit. The same is also true for certain chemotherapies. So having pharmacogenetic information available, I think, would help the physician better prescribe just at a basic level.
The technology will make it possible to diagnose particular genetic diseases, specific forms of cancer, or resistant strains of bacteria. Microbiome analysis is kind of a new area that’s emerging out of research, which is going to be even more unique to every individual. So I think medicine is going to continue to get more and more personal, and that’s good for more-effective treatment. Availability of a diagnostic NGS system is a positive step along that path.
CLP: What do you consider the next steps in the evolution of NGS—NGS2, if you will? Are there areas that offer targets for further automation and elaboration?
Heath: Cancer is challenging because a lot of the solid tumor samples come out of formalin-fixed, paraffin-embedded tissue, which isn’t the best environment for DNA. But we’ve been working on ways of overcoming some of the problems that occur in that space, and I think that will become automated.
Most of the sample preparation is contingent upon the abundance of the sample and the enrichment characteristics required to derive the sample. But people have been working on this for some time now, and I think these problems will be solved. Solving the sample prep and data interpretation issues will happen very quickly, and we’ll see this technology move even more rapidly into the clinical space.
CLP: How rapidly do you see NGS offering a big-data approach to population level data, as a contribution to personalized medicine? Do you think that approach will develop quickly now that the system is available?
Heath: Yes, I do. We’re seeing a number of large-scale projects and major hospitals that want to sequence. For example, hospitals are setting targets for when they want to sequence all incoming cancer patients. I think that’s the right thing to do; it will give them much richer information.
The analytical tools available in other spaces need to be customized to address the particular needs of healthcare, but the problems of big-data analysis have been solved by tech companies for quite some time, and now those solutions are making their way into healthcare. There are also lessons to be learned from the imaging space. An MRI, CAT scan, or PET scan generates tremendous amounts of information, all of which has to be collated and analyzed to get to something that’s going to benefit the patient. Accomplishing all this is not without precedent, and the time is right for acting on it.
CLP: Now that a diagnostic NGS system is available, do you think investors will support the field? Is the pace of R&D likely to increase as a result of greater funding and availability in the clinic?
Heath: Even under a condition where funding is static, I think we’ll see more of an allocation toward translational medicine—and particularly sequencing. As a technology, sequencing is well positioned because it provides so much information. From the perspective of those who are conducting R&D to create new assays, it’s simpler to collect all that information and sort it out later, rather than taking a trial-and-error approach—creating a test, having it fail; creating another test, having it fail; and so on. Sequencing offers a more efficient way of conducting development and, as a consequence, I think more people will look at the space.
CLP: Is the clinical community ready to adopt NGS systems, and to incorporate them into the daily practice of diagnosis and treatment design?
Heath: Yes; that is definitely happening now. The first movement into this space was for cases of pediatric genetic disease, where clinicians had real challenges diagnosing what was wrong with a child. Children were being sent on diagnostic odysseys where they were bounced from specialist to specialist, and maybe a few tests were run. But whole genome sequencing can really shed a lot of light onto all the possibilities for that particular child.
The next move was in the direction of oncology applications, especially for people who had already been through the standard of care. The clinicians were looking for experimental protocols, so in some cases they would perform whole genome sequencing and try to analyze what mutations were relevant to a particular tumor.
We’re starting to see NGS be more broadly adopted in the professional community. One area that has really taken off is noninvasive prenatal testing. In that space, we saw in the span of about two years the Society for Maternal-Fetal Medicine and the American College of Obstetrics and Gynecology come out in support of noninvasive prenatal testing as part of their guidelines. Those guidelines moved very quickly, and reimbursement also got in place very quickly, because it’s just a better procedure than going directly to amniocentesis, and it minimizes the risk to both mom and the baby. When the benefits are realized quickly, things can happen fast.
CLP: I presume clinical adoption is somewhat field- and specialty-specific. You’ve mentioned cancer and prenatal testing as areas that are already on the upswing; presumably others will join as appropriate applications are developed.
Heath: Yes. I’m constantly amazed by the innovation that comes out of the research community. A lot of our collaborators will come up with a breakthrough in a particular area, and then it can move into the clinic quite quickly. Noninvasive prenatal testing wasn’t really on anybody’s radar, and then all of a sudden there were a few breakthroughs, and the next thing you know we’ve got professional endorsements and reimbursements in place.
The old paradigm of taking forever to get through FDA, to get reimbursement, and to be accepted into clinical guidelines is changing. This technology is adding so much value that people are willing to adopt it quickly. Today’s healthcare’s challenges are so much greater than those of the past, and practitioners need the right tools to get answers to their questions.
CLP: When and how will we know that we’re on the right path for building a personalized healthcare system?
Heath: You can see rapid adoption in certain areas, such as the use of electronic medical records (EMRs). When you visit your physician, it’s readily apparent whether he’s got an electronic medical record or is still using a paper filing system.
But I don’t expect the adoption of NGS systems to bring about a big change overnight. These conversions are happening behind the scenes, and they’re happening quietly and quickly. I don’t think we’re going to see some big tipping point, so that we can suddenly say ‘All right, now we have personalized medicine.”
Rather, I think the transition is happening in particular areas already. I anticipate that it’s going to continue growing, and I think consumers will start to demand it more and more. Everybody is online, everybody is aware of the technologies, and everybody is aware of the benefits. I expect this change to accelerate.
CLP: Exciting times at Illumina.
Heath: Absolutely; 2013 was a great year, and we look forward to 2014.
