IN PERSON
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Shuqi Chen, PhD, is the founder and chief executive officer of IQuum Inc. (Boston). IQuum’s lab-in-a-tube
technology is based on his vision and approach to biological sample
processing. A former faculty member
at Harvard Medical School, Chen received a PhD in medicine from
Hadassah Medical School at Hebrew University (Jerusalem, Israel).
He can be reached at
shuqi@iquum.com.
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Today, detection technologies are often viewed by IVD manufacturers as more than just isolated techniques. In an effort to make methods like PCR more widespread, many companies have begun to define them as complete systems, with the ability to handle testing from sample preparation to result. These systems, which could be processed by small hospitals, and even physician offices, would not only make complex testing more affordable and flexible, but could also provide an incentive for manufacturers to expand the menu of tests offered.
To learn more about the changes taking place with detection technologies, IVD Technology editor Richard Park spoke with Shuqi Chen, chief executive officer at IQuum Inc. (Marlborough, MA). In this interview, Chen discusses the technological improvements of next-generation diagnostics. He also talks about the decentralization of testing, the role of automation in IVDs, and the importance of educating physicians and third-party reimbursers about new diagnostic technologies.
IVD Technology: What have been the most significant advances in detection technologies over the past few years?
Shuqi Chen: The most significant progress is that almost 15 years after its development, PCR technology, and real-time detection in particular, have entered the diagnostics marketplace and have been adopted by sophisticated clinical laboratories.
It’s exciting to see a technology go through a long period of development and validation and then move to clinical applications. This has been the most important transition from technology to application that I’ve seen.
In this process of moving to clinical applications, I believe real-time PCR technology has really proven its value. By detecting a pathogen or disease state at the nucleic acid or genetic level, this technology can provide much higher specificity and more clinically useful information. For example, we can detect not only if a bacteria is present, but also if it is resistant to specific drugs. Additionally, because of target amplification, higher sensitivity can also be achieved. Overall, I believe that the application of real-time amplification and detection technologies to IVDs not only enables better detection capabilities in certain applications, but also opens up many new applications for diagnostic and patient monitoring.
How has real-time PCR been developed as a detection technology for IVDs? How has it been made more effective for clinical applications?
There were three critical developments that have propelled real-time PCR to its current application in molecular diagnostics. The first development was the invention of PCR 20 years ago. At the time, PCR was used in the lab to exponentially amplify nucleic acids. This represented a big step forward for molecular biology, but the process was still quite cumbersome; a water bath and add polymerase had to be used with each cycle to perform the reaction.
The second critical step was the development of thermal-stable polymerase and the automated Peltier-based thermal cycler. This development made PCR significantly easier to perform, and at this stage PCR started to find some limited clinical applications outside the research field. At that time, some 10 years ago, gel electrophoresis was the main readout or detection format, and this required the PCR tube to be opened, with the potential of releasing amplicons. This presented a cross-contaminant issue, which can lead to false positives, and separate rooms had to be used for pre-PCR prep, PCR, and then post-PCR gel detection.
The third development, that of real-time or end-point detection chemistries and instruments, allowed amplification and detection to occur in one tube, and thus substantially reduced the cross-contamination problem. This made real-time PCR much more reliable and applicable to clinical use. Other developments, of course, such as hot-start polymerase and UTG treatment to digest amplicon, have also been made to make real-time PCR more robust and allow its reliable operation in the clinical laboratory.
Challenging Traditional Technologies
What are some of the latest trends in developing detection technologies?
There are many. One example is microarray technology. It has proven its capability in the research field and is currently trying to find clinical applications. Especially in recent years, people have begun to gain a sense of how to use this technology and to further its clinical utility.
Another trend is the development of alternatives to PCR. Amplification technologies such as transcription-mediated amplification (TMA) or NSABA have also been proven and found their way to the clinical laboratory.
In addition, many other molecular-amplification technologies are under development, of which most are isothermal based. At this stage, the versatility of these technologies is still being demonstrated. I’ve seen lots of good data from these new technologies, but have also seen some technologies that are limited to only one type of target amplification or one type of condition. So, there’s still a while to go before these technologies become versatile and robust. The medical diagnostic industry is quite conservative. It usually takes a long time to get a new technology accepted and proven. The history of PCR or TMA shows that this can take more than 10 to 15 years.
What advantages do these newer technologies have over the detection technologies widely used today?
Microarray technology provides significant values for high-level multiplex detection, which opens new opportunities to apply this technology, particularly for disease or genomic screening. However, the challenge in using microarrays is how we can handle the significant amount of information that is generated per test and how a physician can translate this mass of information into clinically relevant and actionable intelligence.
In terms of alternative amplification technologies, the question to ask is how these new technologies can be 10 times better than the proven one. Once technologies like PCR are proven and accepted, the trend is that we will use it as much as possible, until a new technology proves itself to be 10 times better. So far, based on what I’ve seen, there hasn’t been a new technology that is 10 times better than real-time PCR.
For example, people sometimes say that traditional real-time PCR is too slow, and rapid amplification chemistries have been developed over the last few years which can generate a signal in 5 or 10 minutes. But PCR is also being refined to improve its speed. IQuum has itself developed a very quick PCR that can complete 50 cycles in 12 minutes while maintaining PCR efficiency and reliability. Many companies have also been developing fast PCR polymerases and reagents. So now, these new developments raise the bar for alternative amplification technologies, and these developers must face the competition of continuous improvement in existing technology.
Another issue is basic intellectual property. For old technologies, the basic patent protections may have already expired or had a certain period of its patent term pass, whereas patents on newer technologies may still have significantly longer terms. When a company selects a technology platform, it has to estimate and balance how many years of the patent term remain, the cost of in-licensing, and the cost of further developing or proving the technology before products can be released. Selecting a new technology means a company may have a commitment to pay royalties over a longer term and also spend the money upfront to develop and validate the technology, as well as get market acceptance.
Overall, it’s not so easy for a new technology to compete with an existing and proven technology unless it’s 10 times better. The key is in how we can find a technology that is 10 times better, and not just a “me too” or marginally improved technology.
What are the primary challenges that IVD manufacturers encounter when developing detection technologies for their products?
IVD manufacturers realize that a detection technology alone is often not enough to satisfy the needs of the customers. The end-users are looking for an integrated solution; that is, a sample in, results out, kind of detection system.
The first challenge is automation. While real-time PCR has integrated the amplification and detection at the back end, integrating sample prep with detection at the front end remains a significant challenge.
The manual processing that is currently needed for many nucleic acid tests forms a barrier for entry to molecular diagnostics. Because of the facility and skill level requirements, only 7% of the hospitals perform molecular diagnostics in-house, and the others all send testing out to centralized or specialty labs. This is analogous to radiological readout for immunoassays. The skill level and laboratory conditions required to handle radioactive labels for immunoassays severely limited the use of immunoassays, and it was not until the use of colorimetric detection that immunoassays became applied and used widely. The automation and integration of all the steps of nucleic acid testing is likely to have the same effect; that is, to democratize molecular diagnostics and allow nucleic acid testing technology to be more accessible.
The second challenge is ensuring the quality of the result. Companies need to constantly push on sensitivity, specificity, and time to result as well as address how to avoid contamination from the environment to the samples. This is more so for an integrated system where avoiding cross-contamination and contamination from sample inhibitors is more critical.
Another challenge is to search for new and clinically useful tests. In contrast to immunoassays, molecular diagnostics have a much wider reach and can detect genes, single nucleotide polymorphisms, viruses, and bacteria. As a result, the test menu is much longer and easily reaches more than 1000 tests. But the demand for most of these tests is much lower, and therefore most of the molecular diagnostics menu consists of low-throughput esoteric tests. Currently, the market is mainly focused on a small number of high-volume tests, such as for HIV and HCV for which the liquid-handling systems are ideally suited. This leaves the large and growing number of esoteric tests underserved because there is not an automation platform that can be adapted to such low-throughput tests. They end up being performed using manual processing or not offered at all by a lab. So how to automate the increased number of low-throughput tests in a random-access and easy-to-use manner is another critical challenge.
How can manufacturers overcome these challenges?
Different companies have different approaches. The large IVD companies are already successfully overcoming the challenges of automating high-throughput tests.
By further improving their reagents and developing automated liquid-handling systems, these companies have already put products of high clinical utility on to the market, such as their HIV-1 viral-load tests.
At the same time, while large companies are focusing on the high-volume centralized testing market, several small and midsized companies have started to put a vision together for the decentralized molecular diagnostics market. This group of companies is more focused on the smaller laboratories, regional and community hospitals, and, down the road, on physician offices. They are developing new chemistries and technology platforms that address the issues of low-volume tests.
Molecular diagnostics are playing an increasingly important role, not only in the IVD industry but also in healthcare in general. How have developments in molecular diagnostics affected the development of detection technologies?
Molecular diagnostics has made the detection chemistry more robust and stable. But as mentioned earlier, the IVD industry is very conservative. It looks at new technologies constantly, but does not adopt a new technology and convert it into a new product until the technology is proven. So I see that it’s the other way around: New technology development is driving molecular diagnostics, instead of molecular diagnostics being the driver.
Simplifying Testing
What sorts of detection technologies has IQuum been developing?
At IQuum, we’ve developed the lab-in-a-tube technology, which is a platform to automate proven assay chemistries and detection technologies to enable sample-to-result testing. The lab-in-a-tube technology integrates sample preparation, which includes target enrichment, purification, inhibitor removal, and DNA extraction, followed by amplification and detection in one closed system. This technology also provides increased assay speed. Our goal is to complete the assay from sample to result within 30 minutes to 1 hour, and our internal development has proven this capability.
What unique challenges do IVD manufacturers encounter in developing detection technologies for point-of-care systems?
Compared with immunoassays, molecular diagnostics are much more complicated, sensitive to sample inhibitors, and are labor intensive, especially the sample preparation steps. As a result, current nucleic acid testing has to be conducted in complex laboratories by highly trained technologists.
To conduct molecular diagnostics at the POC, we need to simplify this complicated processing so that a minimally trained end-user can easily and reliably perform the test in a nonlaboratory environment. This means a high level of automation that requires no manual or technical processing by the user. This also requires a closed system to avoid cross-contamination. Additionally, internal controls and diagnostic capabilities need to be built in to allow a null result to be reported in case of system, user, or reagent error. Random access and rapid assay speed are also critical to allow a test to be started without batching and results to be returned while the patient is waiting. System integration and size are also important. Small, integrated systems with onboard screens, embedded processors, data entry means, and network connectivity are ideal to increase reliability and usability. Developing such an easy-to-use, automated, rapid, and fail-safe system is highly challenging but will not only open up the POC market but also the molecular diagnostics market in general.
Has IQuum established any partnerships or strategic alliances with other IVD companies to develop detection technologies?
We have been engaging in discussions with several industry leaders. The IVD industry landscape is currently changing to integrate patient monitoring, medical imaging, and in vitro diagnostics. This transition has highlighted the need for enhanced decentralized nucleic acid testing capabilities. Right now, substantially all hospitals have their own ECG systems and many have CT scanners, but only 7% have their own molecular laboratory. To fully integrate patient monitoring, imaging, and diagnostics, in-house testing capabilities are needed.
Most IVD companies today have developed internal solutions to address the high-throughput market, but have also recently taken notice of the potential of the decentralized nucleic acid test market.
Building Next-Generation Diagnostics
What challenges will IVD manufacturers have to overcome in developing detection technologies?
We need to be more focused on physician education and how to apply the increased information gained from new technologies to patient treatment. For example, physicians understand the concepts behind pharmacogenomics. But they still have questions about how to use these tests, and what value they provide. That’s one challenge. We need to educate the market more on how to use these newly developed detection technologies.
We also need to consider third-party reimbursement for such tests. Let’s again take pharmacogenomics as an example. Currently, some reimbursement policies specify the order of medications that a physician must prescribe to determine which medicines are effective for a particular patient. Although pharmacogenomics chips are now available which can make the drug selection process more efficient, physicians might still be bound by such policies. As such, these third-party payment policies need to be revised or put in place to allow these new tests to become more widely adopted.
You mentioned earlier that the IVD industry is conservative when it comes to adopting new technologies. How does one go about educating the market and convincing companies that these new technologies are better and can improve their products in the long run?
I think you first have to sell the industry on the long-term vision of the market. Because of the long term of technology development, technology developers need to convey to companies how this technology can meet the future and changing needs of the market.
Second, I think you have to demonstrate to the industry that the technology works with competitive advantages and that the products can be sold with a reasonable margin. As we discussed before, technology needs to be proven before it will be adopted by the industry, and selling the products is the best way to prove the technology.
Most importantly, you need to find a killer application that can demonstrate the value of the technology to healthcare. This value proposition is critical to convince the market to adopt the technology and apply it more widely to the clinic.
Considering the potential changes and the needs of the diagnostic testing market, what new trends can we expect to see in the future in the area of detection technologies?
One trend is the increase in multiplex detection and how real-time detection technologies can be further developed to cover the medium multiplex level. Currently, most real-time PCR is limited to four-plex detection, which is sometimes not enough when you need to detect one panel of perhaps six or eight targets. We have started to see the commercialization of six-channel real-time thermal cyclers, but this multiplex number will most likely continuously increase going forward. Going forward, I see that the diagnostic market will need technologies capable of handling the medium multiplex level, say 4 to 20 targets at once.
The market is also constantly pushing for more-rapid time to result. This is not only for near-patient testing, but also for high-throughput testing in centralized laboratories, where faster testing can significantly increase productivity and simplify lab management.
Other new technologies such as isothermal amplification and single-molecule detection will also mature over the next 5–10 years. I firmly believe that fully automated, easy-to-use, decentralized testing will be further developed and will become a big trend in the next five years.
More and more, people are defining detection technology from sample preparation to result. From the user’s perspective, detection technology means sample in, result out. I think this concept will continue to aid the development of a wider range of technologies.
