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Q&A: Life Tech CMO Paul Billings on Moving Next-Gen Sequencing from the Bench to the Bedside

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Billings2.jpgName: Paul Billings
Title: Chief Medical Officer, Life Technologies
Experience and Education:
Director and CSO, Genomic Medicine Institute, El Camino Hospital
Senior vice president for corporate development, Laboratory Corporation of America
MD, Harvard Medical School
PhD in immunology, Harvard University

As Life Technologies' first chief medical officer, Paul Billings is shaping the company's strategy for moving into the clinical space. Billings joined Life Tech last fall and describes himself as the firm's "senior physician." Clinical Sequencing News spoke with him last week about how the firm is preparing to move its sequencing platforms into medical applications. Below is an edited version of the conversation.


How is Life Technologies planning to evolve from being mostly a provider of research tools to a provider of tools for medical applications?

We are in the beginning of moving our fundamental platforms — whether our qPCR activities or our sequencing methods and products — into more applied spaces, and the ultimate applied space, I guess, is human health. I would not say we are starting at zero; we already have approved products that are being sold in Europe and in the United States that have human health applications, but we will organize and emphasize that more. One of the things [Life Tech has] done is to hire me — I'm influencing the company when opportunities arise to engage in human health applications.

In addition, you'll find that our applied businesses will continue to evolve. We will have a core life sciences business in one operating unit, and our applied businesses — including our human health and molecular diagnostics businesses — in another unit. That will probably come about over the next few months to a year.

What products for human health applications do you already have?

As an example, we have a HER2 diagnostic product, which is CE-marked and approved by the FDA. [That test analyzes tissue sections using chromogenic in situ hybridization, or CISH.] We also have a BCR-ABL quantitative PCR test [to look for a translocation occurring in chronic myelogenous leukemia] that is CE marked. Our 7500 Fast Dx Real-Time PCR instrument received 510(k) clearance from the [US Food and Drug Administration for use with the rRT-PCR Flu Panel] three years ago.

We have plans not only to expand our diagnostic assays, like the HER2 CISH assay. We are in the process of getting FDA clearance for both our 3500 Genetic Analyzer and for our ViiA 7 real-time PCR system. Those will be both submitted within the next 12 months, with assays.

Where do you see the most promising applications for Life Technologies' next-generation sequencing platforms?

We have the whole gamut of sequencing technologies that enables … sequencing to leave the lab and enter the clinical market space. We have the gold-standard confirmatory technology in our Sanger CE sequencing platforms, which represent, by far, the majority of clinical utilization of sequencing around the world. We believe that CE sequencing will be the backbone of confirmatory clinical sequencing and will remain the primary indication for selective, very targeted sequencing in the future. In addition, we have our SOLiD platform, which is appropriate for whole-genome analysis. Its very high throughput and large volume of reads allow it to be exceptionally accurate in certain parts of the genome that are harder to read and maybe clinically important. And finally, we have this revolutionary technology, the Ion Torrent platform.

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Life is uniquely capable of providing an end-to-end solution. And by that I mean sample prep, a first-pass sequencing assessment, a confirmatory sequencing assessment, and then informatics, to allow the analysis of the nucleic acid reads from the machines and then the annotation and assessment in comparison to other people's clinical experience, and then the delivery of that information in a usable fashion to a treating physician.

Can you provide some examples of where you see the most appropriate initial clinical applications of these platforms?

Life creates research-use-only instruments at this point. We have limited approvals on some of our instruments already. The FDA has made it clear that research-use-only instruments are supposed to be used for research and not for clinical applications.

But many laboratories are already using your sequencing instruments for clinical tests.

That's correct. I am aware that our CE platforms are used widely for the diagnosis of infectious diseases. There is a company called SmartGene that provides [informatics] services to reference labs and other labs around the world, taking mostly CE sequence and helping the laboratories make difficult infectious disease diagnoses. In addition, Ambry Genetics uses our CE platform for cystic fibrosis diagnosis, and Myriad Genetics uses our CE platform for BRCA analysis. Those are currently prime examples of the use of what we might call traditional sequencing technologies in the clinical setting.

In terms of next-generation sequencing, I believe that the early triumph of it will be in two fields: genetic disorders and cancer. We recently published, in collaboration with Richard Gibbs at Baylor [College of Medicine] in Houston, the sequencing of the children of one of our employees, our chief information officer Joe Beery (CSN 6/15/2011). I think there are going to be many examples of families [with children with genetic disorders] where we will find that the sequence reveals they have, in fact, a rare mutation, and this will lead to better classification of those individuals' conditions, and in some cases, as in the Beery's case, it will suggest treatment modalities that were not necessarily on the menu.

The second area is cancer, where we are participating through collaborations with [the Translational Genomics Institute] and, more recently, at the University of Oxford in England and at Fox Chase [Cancer Center] in Pennsylvania. We have a variety of projects that are showing not only that there are lots of mutations in tumors that are unexpected, but some of that information will lead to new treatment pathways that were unexpected. Some of this will also turn into clinical utility.

Exactly how Ion vs. SOLiD [will be used], and how those results will be confirmed with CE or PCR, that's all being worked out. I don't think there is a consensus yet.

It seems like Life Technologies is mainly engaging in collaborations with centers using its technologies for clinical research. Is this your general strategy, and are there other such partnerships?

Yes, there are several others that we have ongoing collaborations with, for example with the Knight Cancer Institute in Oregon.

Our strategy is, we are not a CLIA lab, we are not ourselves offering cancer sequencing. We don't do that for a couple of reasons. One is, there is a regulatory issue there. If you are an instrument producer and also a lab, you have a problem with how much you can promote your own instruments at some level. So there is a regulatory gray area where some of the other entities in our sector are playing around in, and we don't want to play around in there.

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The second reason we are not currently a clinical laboratory is that we're not really experts of that, and we believe that to do it right, you need significant clinical laboratory expertise. Since this is not our bread and butter, we are letting others do it.

And then the third reason we are not doing this is because it's very early on to be settling on methods for the production of the libraries, for the selection of targets, for the sequencing protocols, but most importantly, for the bioinformatics on the back end. There may be many solutions, and many people are very creative in producing software. These are areas where we have some expertise but we also recognize that within other bioinformatics outfits within academia and biotech companies, there may be additional important expertise.

For instance, the methods applied for, let's say, monitoring cancer using nucleic acid in the blood may be entirely different from those for a saliva sample taken from a child to diagnose a metabolic or genetic disease. It's going to take many creative people to identify the best platforms, the best protocols for such an analysis. We want to enable a broad swath of investigators, translational scientists, and CLIA labs to work on this, staying within the FDA regulations.

How are you planning to approach regulatory hurdles that might be in the way of introducing sequencing-based tests to the clinic?

We have an aggressive schedule of submitting our key platforms — including Ion. Ion will be submitted to the FDA over the course of the next couple of years. We want our platforms and our products to be approved because we believe that this will allow very broad-based distribution across the world and will make the benefits of these technologies most broadly available.

We will be in discussions with the FDA about what the most appropriate regulatory pathway is. We hope most of the [applications] will be 510(k)s, but I could imagine there will be a couple of [pre-market approvals] in there.

Step number two is, I have for a long time been engaged in Washington at the higher levels of [the Department of Health and Human Services]. In the future, I hope to be more engaged in helping the FDA understand the power and meaningfulness of the advances in nucleic acid analysis, and to recognize that these are rapidly evolving platforms. Both cancer patients and patients with genetic disorders, these people are ill now, they need the insights that these platforms can deliver. We have already had discussions with the FDA, we hope to have more to help them educate themselves and then to engage in a productive discussion with them.

And then I'm also working with other organizations in Washington; I'm a member of the roundtable on genomics of the Institute of Medicine. In general, we're trying to create an environment so that the regulators both understand the power and the rapid movement of these technologies and also can act in their appropriate regulatory capacity to ensure the quality.

Where do you see the missing pieces for sequencing-based clinical tests?

I would say the major hole in sequencing application in the clinical setting is demonstration of clinical utility. We need much more translational medicine clinical activity, many more clinical trials, in which the groups that use sequencing information as a pivotal aspect of the care need to show that the information and the cost of generating it is valuable compared to the way we do things now, or changes substantially the lives of the people who are having this done.

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What's still missing on the technology side —both on the sample prep end and the information technology and data interpretation end?

In terms of sample prep, we have simplified the preparation of biological material for sequencing in our Ion OneTouch platform. The problem remains that for certain kinds of genes, certain parts of the genome, there may be special challenges to preparing the DNA. We are looking for a one-touch, rapid, automated preparation platform for whole exomes, and after that, for whole genomes. We are working on that; we think that it needs to be delivered, but exactly what the chemistries and processes for that are to give you a uniform result across the whole exome or genome are not yet worked out. There are obviously many other entities out there in the world — NimbleGen, Agilent, and many other smaller companies. We're working with or interested in all those guys and what they have to offer.

You asked about the informatics on the back end. There are many issues embedded in that question. The first is the quality of the raw sequence coming off the sequencer. The second step is assembly and variant calling. And then the third step is the annotation of those variants for clinical use. At present, we have focused on the information coming off the machine and its use in assembling a sequence and producing a variant file. The current iteration of that is our LifeScope product [for SOLiD], a new version of which was recently released. We will continue to invest heavily into making that as simple and as user friendly as we possibly can.

Because I believe that the Ion instrument is going to become so ubiquitous, I think we have to take LifeScope up a step, because we are going to need to deliver some of the capabilities of LifeScope across a variety of laboratory situations, and there is going to have to be storage of that information, and creation of variant files on steroids, really. We are working very hard to develop that capability for both SOLiD and the Ion instrument.

There has been an enormous amount of activity both within Life and in the community on this question of curation and annotation of information. I believe there will be a number of solutions in that space. Life intends to offer an end-to-end solution for our CLIA lab customers, with appropriate regulatory approvals and oversights. Over time, we will participate in [developing] or deliver to our customers what we think is best in breed in annotation and other kinds of informatic analysis that will then deliver to the clinical provider a report that they can then further analyze and customize for the clinical situation.

Absolutely essential to this process is the delivery of controls and standards at virtually every step of the pathway, from creation of the libraries and target selection through the sequencing and the quality of the information coming off the sequencer to the informatics. Life has recognized that for several years, and we acquired one of the leading controls and standards companies, AcroMetrix, a few years ago especially for this purpose.

How are you paving the way for reimbursement from health insurance companies for sequencing-based tests?

As part of my role as chief medical officer, I have been engaged in discussions with officials at the [Centers for Medicare and Medicaid Services] and with major third-party insurers to
explain the technology, where we think it needs more clinical trials, where it may be quickly adopted into clinical use, and to engage in proof-of-principle collaborations with them.

If you think about it from the payors' point of view, for instance, the provision of biologics [for the treatment of cancer] is an enormously important and hopeful but also extremely costly development in cancer care. How to use the biologics appropriately and effectively will be a very important question.

Also, as the Beery story and others illustrate, families with genetic disorders often go through a medical odyssey, going from provider to provider, not getting particularly insightful diagnostic or therapeutic advice. Sequencing will for some of those families change the whole ballgame, and the payor can focus the care much more quickly and doesn't pay for redundant imaging studies or other diagnostic studies, and that's a huge saving for the payor.

I think the potential for focusing care and for technology-driven second opinion services with the payors, those are both areas that are likely to yield results.
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I'm curious why you did not mention genetic carrier screening, prenatal testing, or neonatal testing as potential application areas for next-generation sequencing.

Those are screening technologies, for the most part. I believe that the standards of evidence and the cost-effectiveness of screening technologies will require a level of proof and a level of rigor in the instruments and the quality of the data that will take longer than the applications to people who have already had illnesses.

Frankly, it's just my philosophy that the first order of the healthcare system is to take care of the people who are sick. We all recognize that the promise of personalized medicine and genomic medicine is in early identification of those at risk, and then the prevention of further complications and illnesses of those at risk through effective preventive therapies. In many cases, we don't have that information yet. So I think that's going to be slower to develop.

I do not discount the large [potential] impact of, for instance, the application of sequencing in newborn testing. We already test newborns for many disorders now. The ability to do the whole exome or whole genome on a newborn will be possible very shortly at a reasonable price point, and some families may elect to have that as a self-paid diagnostic or predictive test, but to have it as a public health benefit, as we currently provide it in the United States, will require not only further developments of the technology but significant clinical trials.

In the prenatal space, the ability, potentially, to offer a blood-based test that has the same information as an amniocentesis … I believe will come online. I trust that Life Technologies will be a provider of the instruments and informatics and consumables that are required for that. We are aware of [companies] who are developing in that area and have had discussions with them to make sure they are aware of the power and the capabilities of our platforms.

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