Medical Device Link.

IN PERSON

David Persing, MD, PhD, is executive vice president and chief medical and technology officer at Cepheid (Sunnyvale, CA). He can be reached at david.persing@cepheid.com.

IVD Technology: What have been the biggest technological developments and advances in molecular diagnostics during the last few years?

David Persing: I would have to point to real-time PCR as being the biggest advance. The instruments in which the reaction is carried out are self-contained systems for amplification and simultaneous detection.

Because these are closed systems, they don’t require open manipulation of the amplification product. As a result, the technology is much less prone to contamination. Before real-time instrumentation, the problem of contamination had been one of the biggest barriers to the widespread introduction of PCR technology into clinical laboratories.

Labs no longer need to develop special facilities and procedures to address the problem. Being able to carry out PCR in the presence of the detection reagents in a closed system has had a huge impact on diagnostics and has created the potential for the technology to finally enter into the mainstream.

The other big area is multiplexing—the ability to carry out multiple analyses in a single reaction. This allows us to build controls into the reactions for quantitation purposes. In fact, we can build in multiple internal controls at various ranges of detection to allow accurate quantitation over a wide dynamic range. That’s one benefit of multiplexing.

Another benefit is being able to carry out complex analyses of multiple targets, each of which may contribute to a diagnostic picture. To be properly interpreted, some tests require pieces of quantitative information from separate targets.

So, for instance, gene-expression analyses of breast cancer biopsies may require 15 or 20 targets to provide a complete picture of a particular pathological predilection. This is the next complexity frontier, and it shows where the diagnostics field is heading, especially on the oncology side.

What do you view as the latest trends?

I believe that the two areas I mentioned—real-time PCR and multiplexing, either by direct amplification or by use of array technologies—are emerging as trends in the field.

Having said that, it’s surprising that, given how long real-time PCR technology has been available, there are only three FDA-approved tests that make use of it. Even after close to 10 years, there aren’t FDA-approved tests offered by the major diagnostics manufacturers.

They’re coming instead from smaller companies, including Cepheid and Genome IDI, which was recently acquired by Becton Dickinson. Even though the larger companies had early access to the technology and had plenty of opportunities to exploit it, they chose alternative strategies that most in the field now consider to be inferior to real-time PCR. They’ve gotten entrenched with these older methods and it’s taken them time to reinvent the quantitative aspect of the real-time PCR technology.

There are some inherent challenges in multiplex technologies. Are these compounded when developing molecular diagnostics?

There are advantages and disadvantages to the technologies. One of the advantages of working off the same sample is that there is less variability. There’s a built-in control in the system that’s not available when, for example, researchers obtain multiple biopsy specimens and try to correlate the information. In the case of a tumor, different specimens may contain varying amounts of stroma, connective tissue, and other materials that could alter test results.

Of course, analyzing gene-expression profiles from the same specimen also poses a considerable sensitivity challenge. Often, a researcher will have to divide a sensitive diagnostic technique among what amounts to very small quantities of extracted nucleic acid. For a needle biopsy specimen, there is often only a very small amount of tissue that’s actually available. So, the sensitivity requirements for molecular diagnostics need to err on the side of high sensitivity. This provides the greatest flexibility for laboratorians to be able to provide access to diagnostic technologies.

In molecular design, there are also issues surrounding multiplexing. Those of us who’ve developed diagnostic tests for a while all know that a multiplexed assay is a bit like a recipe for a soufflé. Both can be very finicky, and if you throw a new ingredient into the assay—maybe a new primer design or a new probe—it can have disruptive effects.

As a result, the development time for multiplexed assays tends to be longer. If you’re asking for each one of those targets to be quantitative as well, the process can become even more complicated. The need for quantitation imposes an additional requirement for controls, perhaps at the level of each target within the multiplex assay.

Despite the issues and complications related to developing multiplex assays, I do think that’s where things are headed. In general, high-level multiplexing is going to require access to more colors—that is to say, different channels of fluorescence detection in which amplification products can be set during real-time PCR.

We’re going to need dyes that allow more channels to be detected. Cepheid is going from a four-color system to a six-color system by the end of this year. And we are developing our own dyes and systems to go with six-channel detection. There are plenty of examples right now in which the assays that we’re developing are going to exploit all six channels of detection.

Expanding the IVD Market

With these emerging trends, what are the primary obstacles in developing and selling molecular diagnostics?

If you look at the universe of laboratories that are performing molecular diagnostics now, it’s a fairly restricted number, especially those that can be considered full-service molecular diagnostics labs. You’re dealing with only 400 or 500 laboratories in the entire country that fit this category.

Then there is a second tier of laboratories—about 2200—that are still high-complexity rated per the Clinical Laboratory Improvement Amendments (CLIA) standards. Beyond that, there are about 5000 laboratories that have the CLIA rating of high complexity but which do not run molecular diagnostic tests of any kind.

And yet, the 7000 or so laboratories that fall into the high-complexity CLIA rating represent only a fraction of the potential laboratory universe. There are approximately 27,000 laboratories that are able to run moderate-complexity tests but don’t have the specialized facilities and staff to run highly complex molecular diagnostic assays.

So, in terms of what the major challenges and opportunities are, I think the IVD industry has to do a better job of democratizing the technology. We’ve got an ideal platform in real-time PCR, but we’ve not done a good job of commercializing it and reducing the complexity of the testing to make it more available.

I think the next trends are going to be to broaden the marketplace, to allow laboratories that fall outside of the high-complexity categories to run tests locally. These technologies are better for the patient because they return results quicker. They’re better for the hospital because running more tests locally reduces the costs of sending out assays for analysis. In fact, hospitals can turn what has long been a cost center into a revenue center. And I think these technologies are better for the doctors running the tests as well, because they don’t have to wait for the results. The time it takes to transport tests from the hospital to a centralized reference lab can be a major barrier to getting quick test results.

The trends point toward moving sophisticated testing closer to the patient. The key is going to be doing so with- out sacrificing test quality. Another challenge will be using these tests in a moderate-complexity environment, where they can be analyzed by a histopathologist or a surgical pathology lab tech with no formal training in molecular diagnostics and without a specialized facility dedicated to molecular diagnostics. That’s the key in my mind to making this technology a commercial success.

At the same time, I really do think there is increasing justification for bringing the technology closer to the patient. For instance, there may be a real demand for drug-resistant organism testing within intensive-care units (ICUs) and other hospital environments, to know within an hour whether a patient coming into the unit is colonized or infected with methicillin-resistant Staphylococcus aureus (MRSA). The ideal scenario is one where a nasal swab from a patient coming into the ICU can be tested on the spot.

To receive these test results quickly is to be able to generate actionable intelligence regarding management of patients colonized or infected with MRSA. Hospitals can isolate the patient appropriately and minimize exposure of hospital staff and other patients. What often happens now is that patients are admitted without this information, and several days pass before it’s discovered that they’re MRSA colonized or infected. By this point, much of the harm has already been done.

This democratization of the technology is something that needs to happen in molecular diagnostics; it just hasn’t happened yet on the part of many laboratorians because of the turf issues surrounding molecular diagnostics. There’s going to be some resistance because of the restricted nature of the technology. Some may resent the democratization of the technology and view it as competition for their own existing operation. Others may welcome it as a means of expanding their testing capabilities more and bringing sophisticated tests in-house.

So, it’s not going to be an easily solved problem. It’s not going to be an easily solved marketing challenge. But it’s something that’s going to happen eventually.

What can IVD manufacturers do to address this issue?

I think they have to improve their tests from the beginning of the development process. New products need to be designed with moderate complexity in mind. IVD manufacturers need to ask themselves how they can design a diagnostic system that meets the moderate-complexity requirements of CLIA.

That’s the only way to truly democratize the technology. That’s the only way that you’ll be able to see a lab technician run a real-time PCR test for viral meningitis on a sick 3-month-old baby in the middle of the night.

Evening laboratory staff in, for example, the stat laboratory are not necessarily going to be well suited to run a high-complexity test, even in a laboratory environment. The movement toward moderate complexity is going to provide benefits both at the laboratory level and at the point of care.

Manufacturers need to focus on developing tests that can meet these requirements. The requirements for moderate complexity are well defined. Doing so will help open up new markets and benefit patients and doctors alike.

Finding New Targets

Are developments in molecular diagnostics more likely to be driven by traditional targets like infectious or sexually transmitted diseases, or is the field going to start to look more toward genetic mutations as a basis for diseases?

I think there are going to be new opportunities. In the past decade or so, much of the market has been driven by high-throughput, high-volume infectious-disease testing, such as for HIV and hepatitis C.

In the next few years, we may begin to see second-tier diagnostic products being developed for quantitative cytomegalovirus determination, for example. Testing for this type of target is not at the volume of HIV and hepatitis C testing, but it’s an emerging market and a potentially high-margin opportunity. The transplant population, for one, requires sophisticated testing, and with this comes a higher price and potentially higher margins.

On the mutation side, we’re going to see a lot of interest in pharmacogenetic testing. FDA recently recommended that the patients receiving the anticoagulant warfarin be tested for one of the cytochrome P450 enzymes involved in the metabolism of the drug. I’ve heard that recipients of the breast cancer drug tamoxifen may end up getting a recommendation from FDA regarding P450 testing for polymorphisms in the 2D6 enzyme. There’s also news that there are some genetic polymorphisms associated with the enhanced efficacy of Xigris, a sepsis drug from Eli Lilly and Co.

These kinds of diagnostic/therapeutic connections are going to become stronger over the years. There is considerable interest in the connection between the administration and metabolism of drugs, or the association of certain genetic markers with a higher likelihood of side effects from drugs. This area is a huge opportunity for diagnostics that will bridge the therapeutic and diagnostic sides of patient treatment in unprecedented ways. We’re seeing just a few examples of this now, but I think that activity in this area is going to increase.

Going back to my original point about the democratization of the technology, sepsis patients who might be getting Xigris don’t come to the ICU in batches. They come in as single patients, often in the middle of the night, and you can’t wait for a genotyping test to be sent off to an outside laboratory and to come back days to a week later. Treatment decisions regarding dosing or a particular drug selection need to be made much quicker than that.

Drug companies don’t want to be hamstrung by a diagnostic test because that’s going to reduce the likelihood that their drug will be administered in the proper way. So, they’re very anxious to see the democratization of this technology as well. If a test for a 2C9 polymorphism is required to determine the right warfarin dose, and a patient comes in with a pulmonary embolism or deep vein thrombosis, you can’t wait for the test result to be performed as part of a larger batch which is run in the molecular diagnostics lab three times a week. It needs to be performed on a stat basis with timing that’s commensurate with the administration of the drug.

Personalizing Personalized Medicine

How will the continuing emergence of theranostics, personalized medicine, and pharmacogenomics affect the development of molecular tests?

As I indicated earlier, I strongly believe that making the technology for pharmacogenomics more widely available is a critical-path item for widespread patient adoption. If there are pharmacogenetic tests that need to be performed prior to the prescription of a drug—to determine a proper dose or to help identify patients at risk of side effects that preclude them from therapy—these tests need to be available in a manner that’s commensurate with the management of the disease itself.

For a patient with disease A, there may be plenty of time to make these types of decisions, plenty of time to send a test swab to a central laboratory facility across the country and receive a result a week later. But for a patient with disease B, for which a decision needs to be made quickly, waiting this long is just not practical.

My point, then, is that diagnostics manufacturers should focus not just on the target but also on the way the technology is going to be used to prescribe a particular drug.

With pharmacogenomics again gaining attention, do you think that molecular diagnostics will finally get a push to reach its growth potential?

Within transcriptional profiling of cancer, which is a large growth segment, there are lots of opportunities for tumor detection, detection of minimal residual disease, and profiling cancers for the purpose of determining their potential for metastatic spread or susceptibility to therapy. This area has been a direct spin-off of the Human Genome Project. I’d put it on an equal footing with pharmacogenetics in terms of high-growth opportunities for diagnostics companies.

Have money issues such as reimbursement also proven a major stumbling block in the wider adoption of molecular technologies?

It’s the chicken and egg dilemma. We have reimbursement guidelines for quantitative HIV viral-load assays that are pretty reasonable, and manufacturers need to design their technologies to be able to fit within these reimbursement levels. On the other hand, the agencies involved in reimbursement need to recognize the value of diagnostics-driven outcomes and ultimately provide appropriate funding for those tests. They need to realize that in providing better overall patient care, they’re going to save more individualized money by avoiding unnecessary complications.

The Road Ahead

What trends and challenges can we expect to see next year, and further into the future?

I think future trends will include a greater dependence on real-time PCR. It is the most powerful technology out there for quantitation and detection, and it’s the one that has the greatest opportunity for democratization.

And in that vein, I think the trend is going to be toward increased movement of assays out of the high-complexity laboratory environment. We’ll see more movement away from batch-mode testing. Right now, most molecular diagnostics assays are run in batches. However, this often requires patients to wait for results until batch sizes are adequate to justify running a test. This can also restrict the throughput of the assay. Batch-mode tests are typically run by specialized techs in specialized laboratories. This restricts where these tests can be run.

As a result, I think we’ll see a movement away from batch mode to smaller batch sizes that provide faster turnaround times. This could even reach the level of point-of-care-type tests, which are run with built-in controls on a one-off basis.