By: Richard Park

 

Thanks to improved instrumentation and robust chemistries, molecular diagnostics (MDx) is a quickly growing field. Demand for MDx is high; there is currently an unmet need for robust, reproducible tests that provide consistent results within a lab as well as across labs.

To learn more about the role of molecular diagnostics today and in the future, IVD Technology editor Richard Park spoke with Alice Jacobs, MD,founder, chair, and CEO of IntelligentMDx, a molecular diagnostics company based in Cambridge, MA. In this interview, Jacobs talks about trends and technological developments in MDx, MDx's value in battling drug-resistant pathogens, assessing the health of organ-transplant patients, and more.

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

Alice Jacobs: In the past decade, molecular diagnostics has taken off as an industry as a result of major advances in instrumentation, including automation, integration, throughput, and the ability to use the instrumentation in a random access mode. Robust chemistries have been adopted, allowing the ability to quantitate using real-time PCR and other chemistries.

Sample-to-result systems have been embraced, and a broad range of customizable solutions are available for a variety of throughputs to meet the demands of the clinical reference lab. After more than a decade of using molecular methods to diagnose important diseases, it has become increasingly clear that the unmet need is for robust, reproducible, high-quality molecular diagnostic tests whose results are consistent not only within a lab but between labs.

IntelligentMDx believes that the first step in the genetic detection of disease is a better understanding and characterization of the pathogens that impact human health. We're just scratching the surface in our understanding of the complex interplay between exogenous factors such as pathogens and environmental exposures, and their implications in the development of both acute and chronic disease.

The same can be said, of course, for our understanding and characterization of endogenous factors such as genetic mutations or the RNA or protein that is produced from genetic expression. The more we understand the underlying pathology and pathophysiology of disease, the more effectively we will be able to identify the therapeutic targets and biological markers necessary to diagnose, monitor, and treat disease.

There are many examples that have been characterized correlating pathogens to pathogenesis: H. pylori in peptic ulcer disease, HPV in cervical and anal cancer, hepatitis in hepatic carcinoma, BK virus proliferation in renal transplant rejection.

Diagnostic manufacturers took on the risk of developing FDA-cleared tests for certain key markets such as HIV and HPV. However, a gap has developed, and a need has been identified by clinical labs of what additional content could and should be developed to run on systems in their labs. Additionally, there is an unwillingness by some MDx companies to take on smaller markets or more complicated targets. This is understandable given the challenges of clearing a device when there is no predicate or when clinical utility has not been established.

The exciting news is that we at IntelligentMDx have been hard at work for more than five years on the development of a proprietary bioinformatics process that allows for the preselection of metrics, algorithms, and rules necessary to build robust, reproducible molecular assays. This is really the first process to use a systems approach to solving problems in the commercialization of assays. IntelligentMDx is built on an underlying respect for systems biology described by people like Leroy Hood, who pioneered the DNA sequencer and is one of our board members. [Editor's note: See the July 2009 issue of IVD Technology for an interview with Leroy Hood.] We incorporate our knowledge of basic science, applied science, and clinical medicine to solve problems in disease detection.

Built into this process is the integration of inputs from expert end-users to preset the clinical indications and specifications for an assay. IntelligentMDx has been built around a proprietary bioinformatics process that is the first multifactorial computational capability that solves complex problems in assay commercialization.

We have harnessed massive computing power from the genomics arena to produce what we believe are the most clinically impactful molecular diagnostic tests. This power enables a platform-agnostic, chemistry-independent approach to producing assays, which has allowed us to work with the best platforms and the most robust chemistries to solve clinical problems in a more cost-effective manner.

Our assays have been designed to run on existing installed equipment, allowing clinical labs to provide the most robust solutions for difficult assays without necessitating additional capital expenditures. We have solutions that run with similar reaction conditions so that they can be multiplexed, run in parallel, or run separately as needed. This allows a clinical lab to optimize throughput and workflow.

At IntelligentMDx we have worked primarily with real-time chemistries and find our assays perform equivalently on all systems registered with FDA for use in amplification-based molecular diagnostics. The IntelligentMDx proprietary bioinformatics process enables us to build quality into our assays, allowing us to check cross-reactivity and performance of multiplex reactions.

Our bioinformatics process performs this assessment before any wet lab work is done. In addition, our process proactively provides surveillance to preempt and understand the impact of new strain information on assay performance for infectious disease targets. The end result is a robust, reproducible assay that, to date, we have not needed to redesign to enhance performance. In addition, we limit the utilization of enhancements that many have touted to make assays work better but that add significantly to cost.

We also eliminate shortcuts that may impact assay robustness. Everything we do in our design process allows us to consider factors, such as cost of goods, while continuing to maximize performance.

The IntelligentMDx bioinformatics process PriMD has been specifically developed to address complex and evolving infectious targets, such as influenza and HIV. This capability has allowed us to rapidly develop assays in response to emerging threats and to assess the effectiveness of existing tests. We have used PriMD to develop assays, some of which are already in commercial use. However, this summer we had our first major opportunity to give PriMD a real test-drive with built-in time constraints.

Considering the various developments and advances in molecular diagnostics that you've mentioned, and taking into consideration IntelligentMDx's active role in molecular diagnostics, what would you say are currently the latest trends to emerge in the field?

One key trend has been increased efficiencies resulting from following a quality-systems approach to assay design, development, and commercialization. We have a quality system that encompasses our entire business, which is compliant with both FDA QSR and ISO 13485 quality-system regulations. IMDx has been able to demonstrate that by embracing quality, it is possible to build the most clinically impactful and robust assays in a rapid and compliant manner.

Another key trend has been the re-emergence of infectious threats, everything from SARS, avian flu, multidrug-resistant TB, new strains of HIV, and now novel H1N1. We have learned also that these diseases do not respect geographical borders and that global health is really about one-world health. Strains that can be found in Africa might present in the same year in the Midwest of the United States. Swine flu—now called novel H1N1—was certainly spread by commercial travel.

Another key trend is selective pressure applied by the utilization of our arsenal of antimicrobials and antivirals, and the subsequent development of resistant pathogens, as well as geographically imposed genetic drift. MRSA, VRE, seasonal flu resistant to oseltamivir, and now cases of novel-flu resistance—there are many, many indications that the usage of these antimicrobials and antivirals ultimately will result in selection pressure.

Our core product groupings reflect a more in-depth analysis of the selective pressures of pathogens, and our process allows us to be proactive in the assessment of existing assay effectiveness: If a flu test was designed in 2002, does it really contain the primers and probes necessary to identify all clinically relevant strains in 2009?

As an example of one of our new developments and how we are responding to some of the immediate demands, on August 21, the first report was posted in the Morbidity and Mortality Weekly Report (MMWR) dispatch on the CDC's Web site indicating two cases of oseltamivir-resistant novel influenza A/H1N1 virus.

It has been shown that the mutation in the neuraminidase gene is the mutation associated with resistance to oseltamivir, and it has activated the first warning to healthcare providers to consider close monitoring of antiviral drug resistance, particularly in immunosuppressed or immunocompromised patients. These patients were originally documented to be susceptible to oseltamivir, but over the course of their treatment developed resistance. That week we spoke with numerous clinical labs around the country who described to us a strong unmet need for a resistance assay to allow for active monitoring.

Thought leaders we have spoken with feel that it is essential for the clinical labs not only to be able to provide detection but also to take responsibility to provide treatment guidance.

Two additional cases that were reported on September 11, 2009 in MMWR, further support the case for monitoring oseltamivir resistance. Two summer campers were found to have the same H275Y mutation associated with oseltamivir resistance. This second publication again urges healthcare practitioners to monitor for oseltamivir resistance.

On August 14 IntelligentMDx identified and confirmed with thought leaders an unmet need, which led us to initiate immediate development of a real-time PCR assay for the detection of oseltamivir resistance in Novel H1N1 cases. Five weeks later we met with FDA to discuss the assay's consideration for use under the Emergency Use Authorization Statute. We anticipate that this assay will be available for the current season.

We also have produced an assay for infection control. Infection control is an area that is equally moving for me. I lost a patient from a staph infection during my medical training, which is why I started this company.

We have developed an assay that can support hospital infection control practices, allowing hospitals to screen patients at the point of admission. These serious, resistant pathogens can result in the development of severe disease downstream, as well as potentially infecting other patients.

Evidence has shown that even after a hospital room has been cleaned, the occupant is at increased risk of developing an infection if the previous occupant was infected. Our aim at IntelligentMDx is to make this test as affordable as possible, and work to ensure optimum workflow for running the assay such that it can easily be adopted into the arsenal of infection-control practices supported by clinical labs worldwide.

Post-transplantation infectious disease is another major area of our company's growth. One of the best indicators of a patient's health status is the proliferation of certain key viruses that latently infect most healthy people—but only proliferate in cases where a patient's immune system has been suppressed, as is the case with transplant patients. Our transplant assays have been designed to accommodate workflows in labs—that is a key consideration for lower throughput assays. These assays are random access and as such are designed to run under the same cycling conditions, so they can be multiplexed, run in parallel, or run separately as needed, allowing clinical labs to customize the solution. IntelligentMDx has an assay for infection control for the detection of Bordetella, which is also worth noting.

The key in all of this is that when we think about differentiation, we have to think about what is important to the patient, the clinician, and the lab, which means improved clinical outcomes based on the information, and improved process efficiency for the clinical lab and support.

We have produced novel assays that identify each of these issues and build them into the solution.

As I'm sure you are very well aware, molecular diagnostics is an incredibly challenging area, and very complex. With that in mind, what are the primary obstacles—financial, regulatory, technological—that IVD manufacturers encounter when developing molecular diagnostics and in trying to do business in the molecular diagnostics arena? How do IVD manufacturers overcome such challenges?

I think a key challenge for this industry overall—and I think this is something that is on everyone's mind—is that there needs to be an accepted process for establishing clinical utility of new markers.

There was a great meeting with NIH and CDC to look at personal genomics. It is important to have these workshops, not just to get the dialogue going, but to really think about how to move things forward.

I think these workshops would greatly benefit from incorporating assay manufacturers' input as a more significant part of the official program. Assay manufacturers are the entities who take on the risk of commercializing assays for new markers. A shift needs to occur regarding discussions focused not solely on new methodology—because that is the easy part—but on an approach that will produce clinically impactful assays for newly defined biological indications, which I think is what everyone is looking for.

I think a second concern—and much has been written about this—is the issue of increasing regulatory requirements. Certainly to me, having been trained as a clinician, some of these things make good sense. We are required to take an oath: First, do no harm.

This means that with every decision we make, we must put patients first, and we cannot adopt new devices or treatment until they are proven to be safe and effective. I think that quality systems enable a company to embrace safety and efficacy.

We at IntelligentMDx have proven with our own efforts that the most effective way to overcome challenges associated with regulatory concerns is to build quality into products. It is possible to design out many of the challenges in the early stages, and it is essential to design for the end-user. It is important to educate consumers about true product differentiators, such as the great patient benefits of new products, beyond just looking at cost.

I think that we have been able to demonstrate particularly, with some of our new assays like our 2009 influenza assay, that if you work hard to design and use a systems approach to building assays, you can provide clinically impactful results. IntelligentMDx has embraced this quality-systems approach to our entire business and has focused not only on meeting stakeholder requirements, but exceeding them.

Is molecular diagnostics as a field still driven mainly by the traditional targets of infectious and sexually transmitted diseases? Or is the field going to start looking more toward genetic mutations as a basis for diseases?

The answer is yes and yes. There is a lot of room that remains in solving problems in infectious diseases. Until we are willing and able to adopt a symptom-based approach to disease diagnostics, we won't fully realize the utility of molecular diagnostics in solving problems in infectious diseases.

An important aspect of this will be the clinical lab's ability to divide up workflow based on disease area as opposed to type of laboratory test utilized. For example, if a patient presents with presumed pneumonia—cough, fever, chills, shortness of breath, decreased breath sounds on exhalation—the symptom-based approach would be to run a pneumonia assay that would cover all of the likely viruses, bacteria, and even fungi that could result in the patient's particular symptom presentation.

This could not be accomplished if viruses are detected in virology labs and bacteria in the micro lab. If our goal is to put patients first through the clinical lab, the clinical lab will need to be empowered with the resources to bring in the right tools to continuously enhance workflows.

Clinical labs should be commended for the adoption of new technologies despite negative cost pressures in their best effort to put patients first. Cost accounting—in which labs are reimbursed a fixed amount per test—does not allow the support of incorporating more-effective, clinically impactful solutions.

The downstream implications of the utilization of clinicallyi ntelligent tests in terms of cost savings to the overall patient care episode are significant. By investing up front, there is a growing body of evidence to support the massive downstream savings to hospitals and to payers.

And let's not forget the benefit to patients of early disease detection. While we are waiting to dig up the markers to allow us to prevent disease, let's at least try to adopt strategies that allow us to catch things early.

There is a strong general belief currently that there is more value associated with genetic mutations as opposed to exogenous targets such as pathogens. Yet there remains a lack of established evidence to support this.

What you are asking about is distinguishing the impact of exogenous and endogenous mutations on human health. I would respectfully argue that they are equally important, and that an overall better understanding of disease process will allow for rapid development of better tests.

It is the mission of IVD manufacturers to turn these innovations into quality products. Infectious disease is generally simpler, and if we can't get that right, how will we do a good job on endogenous, more complex issues?

Pathogens are continuously evolving, and there is a need for a more-effective process supported by regulators to provide a rapid response. Just as a flu vaccine must be reconsidered annually, we need to consider equivalent guidelines for diagnostics.

Ultimately, it is the responsibility of the IVD industry to provide definitive test results that allow care with certainty. We need to align ourselves closely with academic experts who are at the front lines of solving problems in clinical medicine to establish the guidelines for building new and better assays.

What might be the role of other clinical areas in promoting the adoption and use of molecular diagnostics?

One of the things we're finding is that some of the markets are under-characterized. Some of these markets are well defined, such as blood screening. In the area of infection control, there is a whole slew of pathogens that are important for infectious disease experts and hospital epidemiology programs to embrace as part of best practices for patients.

You mentioned the information exchange between clinicians and IVD manufacturers to address unmet needs and to enhance greater awareness. Do you have any ideas or suggestions for what could be part of that information exchange, or how to build an information exchange for molecular diagnostics?

That is a difficult issue because there needs to be a lot of time spent between clinicians and IVD manufacturers, especially R&D, to understand and define the product specifications clearly. We are seeing marketing considerations and constraints that have been set up in Massachusetts that will certainly be emerging nationwide about how an IVD manufacturer can interact with clinicians. This is something that needs to be worked out more carefully. For us it has simply been our experience attending various conferences and developing a rapport with the various clinicians who are experts in our space—allowing them to be part of the process of developing our assays.

I think there is a lot that needs to be done in terms of developing a better forum for that interaction. That is certain.

As you know, MRSA is a very important issue and certainly something that is considered in surgery theaters and emergency settings now. Could some sort of rapid molecular diagnostic test for use in a point-of-care setting be developed?

We have spent the last several years looking at point-of-care solutions and speaking to clinical laboratories, and one of the great challenges is that regardless of where the device is placed in the hospital, QA and QC are very important. If there is a good workflow in the hospital, such as a pneumatic tubing system, then having those devices within the confines of the clinical lab where they can be monitored more carefully has generally been the preference. It is important that there is an effective workflow to decrease the turnaround time from sample to results, and a lot of that can be done with current instrumentation.

That said, it has become increasingly clear is that there are certain key infections that have been targeted, particularly by CMS, for which hospitals will no longer receive treatment reimbursement. It is essential for hospitals to screen patients at the point of admission to make sure that they are not coming in carrying one of these infections.

Hospitals must control and clear the infection at the door. Whether that solution needs to be right next to the patient remains to be seen.

Some of the buzzwords emanating from the industry lately are companion diagnostics, personalized medicine, pharmacogenomics, and theranostics. How will the continuing emergence of these innovations affect the development of diagnostics? Would you agree that these buzzwords represent very important emerging areas that appear to show a lot of potential not only in the IVD industry but also within healthcare in general?

Testing is essential and can certainly raise awareness of and help monitor adherence to prescribed treatment regimens. According to The New England Journal of Medicine, the cost of nonadherence to medications was somewhere between $100 billion and $300 billion annually, including costs from avoidable hospitalizations and nursing home admissions and premature death.

Being able to reduce medication errors and monitor the effectiveness of medications is certain to ensure better clinical outcomes. The current definition of personalized medicine is too narrow to address the problems that we are trying to solve, which are how to develop more-effective diagnostics and treatment, and how to accelerate and streamline costs associated with discovery and development.

The current definition includes only monitoring endogenous human genetic markers. It does not even include the endogenous markers that are produced from the expression of those various mutations, which are key. Even then you are only at half the story because for individualized medicine or personalized medicine, to be able to offer the right treatment to the right patient at the right time will require monitoring of both endogenous and exogenous markers.

Exogenous markers—also described as surrogate markers— cover environmental exposures and must be included. Within the definition of biomarkers we need to include microbes that take up residence in our bodies and are associated with a broad range of acute and chronic diseases. We are just scratching the surface in understanding how microbes influence the development of acute and chronic disease. These exogenous markers are biomarkers.

We will also need to assess for therapeutic optimization factors, which are the inclusion of such things as detection of antibiotic resistance and virulence, as well as the detection of things like liver enzymes associated with metabolism for specific treatments.

At IntelligentMDx we have built a strong intellectual-property position covering multiplex detection based on important symptom presentations, which covers detection of both endogenous and exogenous markers. There is over a decade of data to support that surrogate markers such as microbes can be the most precise indicators of disease status.

As for biomarkers—the Holy Grail—billions of dollars are being spent to find what we call ‘‘magic biomarkers'' or ‘‘magic markers,'' the idea being that a marker strongly indicates the absence or presence of a disease. However, the majority of disease states are multifactorial, and as a result, we need to use everything in our arsenal to be able to monitor the patient, and we cannot exclude a strong impact of environment on the development of disease states.

We are finding more and more this interplay between pathogens and the development of acute and chronic disease and have built a pipeline of robust products. You can look at some of the great companies in the IVD industry that have been the trailblazers on this, looking at things like HIV genotyping to assess an appropriate therapeutic regimen.

IntelligentMDx is carrying along that mission, and certainly in the near term we have been interested in how we can impact and streamline drug trials—and in the long term have an impact on more-effective drug discovery through a greater understanding of pathogenesis.

That said, we will need pharma to embrace colabeling to support the necessary heavy lifting to establish clinical utility on the complex patterns of endogenous factors that contribute to disease.

We look forward to developing markers for identification of endogenous factors—it would allow us to bring our analytical requirements into a different realm. Our bioinformatics process robustly supports development of endogenous markers. Our continuous surveillance process allow us to incorporate new knowledge to enable ongoing effective decision making about whether the assay can still meet performance requirements given additional information. But again, without the full embracement of colabeling, we believe this is a difficult and uphill struggle.

Looking toward perhaps next year or even five or 10 years down the road, what new trends can the IVD industry expect to see in the future in molecular diagnostics, and what future challenges will emerge?

By embracing quality we will see better results in terms of clinically impactful tests such as measuring a target directly versus by process of exclusion. Given the current healthcare-reform debate, I think that one thing that has been concerning for everyone in our industry is that we can't just cut costs. If we cut costs without emphasizing quality, everyone will lose. It has been proven time and time again that you can actually save money by getting things right up front.

Another thing that is going to be important is really thinking about developing impactful tests that have a global reach—understanding that these diseases do not respect geographical boundaries.

Are there any other comments you'd like to make regarding molecular diagnostics?

This is a very exciting time in molecular diagnostics as customers are beginning to distinguish the ‘‘best'' test from ‘‘a'' test. There are a lot of issues still unresolved around what constitutes the ‘‘best'' test, and these may take a while to resolve.

In the meantime, IntelligentMDx is applying a unique combination of real-life customer needs feeding a systems approach that accelerates the commercialization of high-quality tests. We feel that by building and applying our unique approach, we can have the most positive impact on patients and, at the end of the day, the best molecular diagnostic test is the one that benefits the patient most.