MDx, a shifting technological lineup

Molecular diagnostics companies have laid the foundation for nothing short of a revolution in cancer care – it is time for the MedTech sector to develop tools to make genomic testing accessible to the masses.

Molecular testing approaches like next-generation sequencing (NGS) are outshining more traditional IVD products such as immunoassays, with nearly triple the growth rate of the overall market. When molecular testing approaches were launched two decades ago, the conventional wisdom was that they would replace older testing methods. As it turns out, they have not. But the market for molecular diagnostics (MDx) is estimated at USD 8.7 billion and is experiencing growth that is above average for traditional IVD technologies, according to Kalorama’s annual report. However, the global molecular diagnostics market for cancer care was valued at USD 1.6 billion last year, up more than 10 percent from 2018. That is just a fraction of the entire molecular diagnostics field, but still staggering for a medical arena that is still in its infancy.

It looks even more impressive how few physicians are actually ordering molecular diagnostics tests for cancer patients. Some studies have shown that despite 75 percent of physicians believing that genomic testing improves patient outcomes, only 4 percent routinely order a molecular diagnostic test. Imagine what the molecular diagnostics market would look like if all physicians, who believed in the value of genomic testing, were actually ordering it. How does the market get there? If physicians know patients benefit from molecular diagnostics, why is not it a routine part of cancer care?

Research shows that less than 50 percent of physicians feel confident in their ability to interpret molecular test results, and a mere 10 percent are confident in their ability to use test results to guide the process of prescribing treatment. For molecular diagnostics to truly take off, one need to fix that – with innovations that cater to the clinical setting.

Molecular diagnostics companies have done much of the work already. Almost 100 percent of physicians view molecular risk assessment as having the potential to play a crucial role in determining drug therapies for patients. That is a strong position for companies trying to sell those physicians on new products.

But design is crucial. One need to design out from cancer clinics to create tools that immediately help oncologists treat patients, rather than expect adoption based on the tremendous aggregate potential of whatever companies are selling.

Data will only drive healthcare information, if it is collected. Molecular diagnostics companies have laid the foundation for nothing short of a revolution in cancer care – it is time for the MedTech sector to develop tools to make genomic testing accessible to the masses.

Technology is changing fast
Within the realm of molecular diagnostics, the landscape is changing fast as new technologies threaten to displace mainstays. Hybridization-based testing such as microarrays and ISH are being superseded in clinical practice by next-generation sequencing and quantitative polymerase chain reaction (qPCR) technology.

Nucleic acid microarrays are surfaces with dozens to thousands of microscopic spots, each populated by probes specific to one target sequence within a sample. Genotyping is the main clinical application of microarrays today in various application segments covering noninvasive prenatal tests, postnatal testing, tissue typing, and infectious disease tests, as well as patient genotyping related to pharmacogenomics or rare diseases.

Microarrays are cost-effective, but they have lost market share in many applications. The array format has gradually been superseded in molecular hybridization assays by in situ methods and advanced hybridization technologies.

Molecular diagnostics finds a great deal of application in the human gene mapping process, where extensive research is being carried out to construct a detailed genetic map of the human genome and determine the entire sequence of DNA.

One of the latest entrants in DNA sequencing technology, this method of molecular diagnostics has actually revolutionized genetic research. NGS has emerged as a powerful platform that enables the simultaneous sequencing of millions of DNA molecules. Next-generation sequencing (NGS) is a high-throughput option, with capability to sequence multiple individuals at the same time.

A relatively futuristic technology wherein by utilizing molecular diagnostics, medical treatment is tailored according to individual characteristics of each patient. Therapeutic approaches are being developed, keeping in mind the genetic make-up of the patient so that precise treatment is administered.

Next-generation sequencing is also having an impact. Future markets may be fundamentally remade as clinical sequencing becomes viable for testing in many application areas, including pathogen identification, comprehensive cancer testing, comprehensive genomic profiling (including inherited disease detection), and organ matching. The first NGS system was approved for clinical use by the FDA in 2013, so the market segment is quite new, but a significant industry already exists for LDTs, performed as testing services on NGS platforms by certified clinical labs. The current IVD market for clinical sequencing consists largely of sales of NGS systems to reference and specialty genetics labs, including instruments, library preparation, and sequencing reagents and consumables.

NGS is increasingly used for clinically heterogeneous inherited disorders, resulting in an increase in the number of reported disease-causing genes. Even though the majority of human inherited diseases involve variations in a number of genes, a few genes often interact, leading to overlapping pathological phenotypes. NGS is a powerful approach in the case of heterogeneous and complex diseases, such as in cardiomyopathies, where many genes are involved in a large phenotypic spectrum, because it allows testing of a large number of genes simultaneously in a cost-effective manner.

With all the talk of data-driven innovation in healthcare these days, there is a critical component that is often being left out of the conversation. Collecting data requires building tools that physicians and patients will want to use. Think about the immediate benefits of wearables that alert to physical irregularities or remind of medication schedules. However, physicians are already overburdened with data input, a task that federal regulations prevent them from delegating. It is no wonder that they are resistant to outside demands to collect more data or increase testing – unless it adds obvious value to their clinical care. No one denies the potential value of molecular risk assessment in determining drug therapies for patients. The problem is that healthcare innovators have yet to make molecular diagnostics truly user-friendly.

There is nothing simple about genomic testing. And molecular diagnostic companies are well aware of the challenge they face in trying to make results not only readable but actionable. Their work will allow physicians to identify cancers sooner, personalize treatment, save millions of lives, and hopefully beat cancer one day. But the physicians, scientists, and companies leading the charge on genomic testing cannot go it alone. As elsewhere in the healthcare space, there is a need for developers and designers who can merge their skills with the emerging science and create products that add value to the patient-doctor relationship. For molecular diagnostics, innovation means adding an interactive layer between testing companies and cancer clinics that guide physicians and patients through the test results, drawing on an expanding universe of data to make treatment recommendations and identify targets for therapy. Oncology innovators are already searching for new approaches to collecting data on patients. But an opponent as aggressive as cancer can only be fought with scalable solutions. Experts need to develop tools and services that must be used, if physicians want to claim that they are providing top-flight care.

Without question, the future of rapid, random-access molecular testing is moving closer and closer to the bedside or clinic room. Currently, there are a number of clinical laboratory improvement amendments (CLIA)-waived molecular tests for influenza virus, some paired with respiratory syncytial virus, group A Streptococcal pharyngitis and for Chlamydia trachomatis and Neisseria gonorrhoeae (CT/NG) with excellent analytical sensitivity and specificity. CLIA-waived means that these tests can be performed outside of a laboratory and by non-laboratory staff such as nurses. Studies of these platforms have shown clinical impact for influenza detection in both the inpatient and ambulatory settings. Group A S. pharyngitis (GAS) POC molecular tests are now CLIA-waved, without the need for confirmatory culture of negative results.

Bringing molecular testing outside of the clinical laboratory comes with appropriate concern. First, these assays produce millions to trillions of copies of pathogen nucleic acid. While they are closed systems, there is always the possibility of amplicon contamination from a defective product, and one laboratory accrediting agency has recently added new requirements to this point. To investigate potential contamination, researchers performed weekly swabs of the surface of an actively used POC molecular GAS test and surrounding environment at two different urgent care clinics. They were not able to detect any contamination that amplified via the same test across the 13-week period of the study. Second, as more molecular assays become CLIA-waved for POC use, especially those with multiple targets, the ability to provide diagnostic stewardship becomes increasingly challenging. For example, one of the large syndromic respiratory panels is now CLIA-waved. More data are needed on how these panels are used and interpreted in outpatient and urgent care settings.

Molecular diagnostics in true sense is a transformative technology with revolutionary offerings; however, it faces certain challenges like lack of proper regulatory policies, data archiving tools, high costs, data secrecy, and others. However, a multitude of molecular techniques are now being utilized in the clinical field, hence making it an integral part of clinical practice. Agreed, there are a few challenges, but with the day-by-day advancement in technology, those challenges can surely be overcome.

An evolving landscape
As the landscape of infectious diseases evolves, emerging resistance mechanisms and novel therapeutics for treatment-retractile diseases will require cutting-edge molecular diagnostics to evolve simultaneously. The use of metagenomic and/or transcriptomic data to assess the resistome of a clinical sample requires further exploration to understand whether phenotypic antimicrobial susceptibility testing can ever be replaced, or at least sufficiently augmented, by such techniques. Tremendously promising work is also being done to understand how microbiome influences human health and how that can be manipulated for treatment purposes for multi-drug-resistant organisms as well as C. difficile. The success of fecal microbiome transplants may someday require companion, real-time metagenomic characterization of donor stool, as well as post-microbiome engraftment analyses. Similarly, phage therapy, with or without CRISPR-Cas9 strategies, to combat highly antimicrobial resistant bacteria may require metagenomic analyses to assess efficacy.

Finally, advances in the speed of amplification through techniques like extreme PCR will no doubt lead to a next generation of rapid diagnostics. Technologies will no doubt continue to develop to reach the rapid state. Advances in molecular speed and cost will likely also result in the availability of direct-access CLIA-waived molecular testing that patients can perform in their homes as well as a continuously expanding menu of molecular testing to be performed at the point-of-care, including the outpatient setting. Hopefully, future iterations or new platforms will include smaller, modular, or even reflexive panels that lead to clinically appropriate testing for the right patient populations. Studies on the clinical utility, impact, and diagnostic and antimicrobial stewardship approaches for these types of advances are very much needed.

Outlook
As molecular diagnostics continues to push the boundaries of speed and comprehensive and complex analyses, optimal utilization and impact will require partnership with stakeholders, particularly antimicrobial and diagnostic stewardship programs. The current pace of these technologic advances, and subsequent FDA approval of a subset, has created an unfortunate lag in ability to appropriately steward their use. While many groups have published promising data on effective utilization, the market is far from the optimal state. More data is needed to drive the future use and expansion of these panels, particularly as they move closer to the point-of-care.