Molecular Diagnostics
MDx continues to make inroads into COVID testing
The high demand for molecular diagnostics could seed structural shifts that will have long-term implications for diagnostic-test manufacturers.
With high technological and regulatory barriers to entry, in vitro diagnostics (IVD) has been a relatively high-margin industry, with molecular diagnostics (MDx) being one of its fastest-growing segments.
2020 was set to be a year of growth and innovations in molecular diagnostics under any circumstances. New products, higher growth than other IVD categories, continued acceptance of next-generation sequencing methods were driving. Liquid biopsy technologies and the increased use of predictive genetic tests were and still are areas of anticipated revenue growth. The sudden onset of SARS-CoV-2 and the resulting disease COVID-19 put the world’s focus on MDx in an unexpected way.
The global MDx market, including new tests for COVID-19, exceeded USD 13 billion in 2020, according to Kalorama Information. That is about USD 5 billion larger than 2019, and reflects the large volume of sales for COVID-19 molecular tests in the US and worldwide.
COVID-19 testing is slated to continue into 2021, if the present trends continue. While it is possible COVID-19 tests will be panelized, that is added to existing tests in combination with flu and other respiratory conditions, and while it is also true that the market may not support the kind of emergency crisis sales of 2020, the influence of COVID-19 on molecular diagnostics should last a few years. It already has boosted the respiratory and healthcare infection molecular testing markets and has generally increased public awareness of PCR testing.
The news is not all positive from a revenue perspective. Molecular testing on COVID is paired with declines in more traditional molecular tests as patients avoid doctors and continue to reduce in-person doctor visits. Down but not out segments include cancer, histology, and inherited diseases, which are expected to continue to grow, perhaps surge, later in the year.
Prior to COVID-19, liquid biopsy was one of the stars of this segment. Favorable regulatory policies and promising studies will enhance companion testing. New LDT tests in inherited disease testing in particular, using IVD supplies, which includes non-invasive prenatal testing (NIPT), is driven by the demand in China. Even though the demand is for laboratory test services and not for IVD products, the demand for instruments, kits, and consumables that are approved by regulatory agencies is driving the segment.
However, the market opportunities may be challenging to access by foreign IVD companies because of the regulations promoting domestic companies.
Many of the vendors making COVID-19 tests also make tests for other infectious diseases, such as HIV and zika. Those focused on the novel coronavirus may disappear when the crisis is over, but others may remain. There is no shortage of new competitors entering this market and even if a solution emerges for COVID-19, it is logical to expect that many of these new vendors will continue to develop lab test products for other conditions and some will be on standby with production knowledge and facilities for the next pandemic.
The companies in the molecular diagnostics space will have to plan their next steps very carefully. They have made a lot of money in the boom of the COVID-19 pandemic, but they must be careful not to be saddled with large illiquid material assets for a market that is a fraction of its previous price.
Without question, COVID-19 is the most intensively studied infectious disease in history with >125,000 PubMed citations from January 2020 to April 2021. This contrasts with influenza, at about 8,000 citations, and tuberculosis at 10,000 citations in the same time period. The contributions of molecular diagnostics to COVID-19 assessment toward reduction of morbidity and mortality are widely recognized. Still, the inevitable false negative rates have contributed to a substantial increase in cases as did delays in turnaround time test reporting.
Less appreciated, but perhaps even more important, has been the impact of COVID-19 on molecular diagnostics testing and research for non-COVID applications. In the initial phase of the pandemic, the lack of equipment, reagent capacity as well as insufficient lab environmental protection including personal protective equipment, slowed the deployment of COVID-19 molecular diagnostics while contributing to the stress and exhaustion of laboratory professionals faced with coping with sudden huge and urgent testing demands. Adverse effects of the pandemic on mental health have been universal and similar irrespective of occupation but have been quantified in depth for specific groups, such as high-performance athletes. A collateral persisting consequence was delay in molecular diagnostic testing for other diseases in part because of redirection of resources, and in part from reduction or suspension of other non-urgent care in hospital centers. A less recognized adverse consequence has been on non-COVID biologic research, including molecular diagnostics. Non-COVID research has been hampered for the past year by reallocation of equipment and personnel to COVID-19 studies, supply chain disruptions, and social distancing protocols, particularly in academic institutions. Amongst the sectors most severely affected has been hospital-based clinical research.
Novel molecular diagnostics tests directed toward COVID-19 detection, identification of virus variants, inflammation mechanisms, immune specific effects on lungs and other organs, and currently, vaccine efficacy, have each played major roles in control of the pandemic.
COVID-19 has demonstrated both the power and current weaknesses of molecular diagnostics bioinformatics. On the positive side, the bioinformatics capacity to determine by modeling, potential antigenic sites on the viruses, has led to successful vaccines and rapid detection of viral variants.
However, the COVID-19 pandemic has demonstrated forcefully that lab informatics connectivity, throughout the world, has been woefully insufficient to provide clinical physicians, epidemiologists, and public health professionals the molecular diagnostics vital information on infectivity in a sufficiently timely manner to guide pandemic control.
Nonetheless, the early evidence, such as that from Switzerland that rapid turnaround of molecular diagnostics coupled with rapid contact tracing is effective in control of infectivity, is a powerful stimulus to rectify lab informatics connectivity deficiencies.
The COVID-19 pandemic, as the proverbial ill wind, has opened many beneficial future opportunities for molecular diagnostics. First, the investment and revenue in molecular diagnostics has generated large corporate funds for future investment in better tests and molecular diagnostics tests for novel applications.
Similarly, the pandemic costs experienced by all nations are a huge stimulus to governments to provide incentives for fundamental research in molecular diagnostics science. These investments will have high impact beyond the pandemic as excess capacity can be reallocated to noninfectious medical conditions. The challenge will be to maintain this momentum so that diagnostics capacity can be available for the next infectious disease crisis. Amongst the needs being addressed is RT-PCR instrumentation capable of providing molecular tests in larger volumes with decreased turnaround time.
However, these instruments typically require highly trained personnel and stringent environmental conditions available only in large urban laboratories. To meet public health needs to detect positive cases, expedite isolation of individuals testing positive, and speed up contact tracing, a different delivery model is required, namely decentralized reliable point-of-care testing, with results reporting during the same patient encounter. Although more than 19 different tests have been approved for rapid COVID-19 testing, none yet fully meets the requirements for sensitivity and specificity as well as rapid turnaround time. COVID-19 has accelerated development of a wide variety of sensor-based point-of-care methods, including PCR for infectious disease detection. These advances will facilitate decentralized molecular diagnostic testing not only for infectious diseases but also for many other disorders.
Father of the modern genetics and a leading pioneer of biotechnology
In 1869, a Swiss physician named Friedrich Miescher analyzed the pus that was in the discarded bandages of one of his patients, and discovered that the discharge contained microscopic material. He called the substance nuclein because his microscope allowed him to see that the substance resided within the nucleus of the cells. Then in 1878, Albrecht Kossel was the first scientist to isolate nucleic acid, and went on to isolate the five primary nucleobases later in his career.
At the beginning of the 20th century, the terms DNA and RNA had not yet been invented – but their existence was no secret in microbiology circles. In those early days DNA was known as thymus nucleic acid, because the tissue that was being studied had been extracted from a thymus gland. In a similar way, RNA was known as yeast nucleic acid, with yeast as the source material.
Phoebus Levene identified the nucleotide unit of yeast nucleic acid in 1909, carefully noting the base, sugar, and phosphate components. Then in 1929, while studying thymus nucleic acid, he identified deoxyribose sugar. Leven’s tetranucleotide hypothesis was the first to suggest that thymus nucleic acid was composed of four nucleotide units linked by the phosphate groups – although he thought that the ordering of the nucleotide units was the same in every cell.
It was Nikolai Koltsov who, in 1927, proposed his idea that hereditary traits were carried by two-stranded – or mirrored – molecules, with each strand acting as a genetic template. The very next year, Frederick Griffith performed an experiment using two different but compatible bacterial species, which provided the first real indication that DNA – as it was later known – was the true carrier of hereditary information.
The most common acute manifestation of COVID-19, leading to requirement for mechanical ventilation, is pneumonia but this may be of two types – an interstitial pneumonitis and/or a bacteria-associated bronchopneumonia. COVID-19 infection is rarely fulminant but early stages may go unrecognized particularly in elderly, debilitated patients. Better lab tests are still needed to assess presence, type, and intensity of lung inflammation where patients have suppressed symptoms, and to discriminate between bacterial and nonbacterial inflammation.
While the molecular diagnostics advances have been instrumental in identifying patients and asymptomatic contacts with COVID-19, the tests have not realized their full potential because of inadequacies related to laboratory informatics connectivity and informatics analyses.
Typically, 1–2 days pass before individuals present for testing, followed by 2–5 days for testing to be completed in a central laboratory and results returned. This compares with the estimate that each day delay in COVID-19 test results in presence of fully functioning contact tracing, increases cumulative disease incidence by 28 percent and resource utilization by 33 percent. It is worthwhile reflecting on this deficiency, its massive costs, and potential solutions. Turnaround times for lab tests have been based on past expectations for healthcare in hospitals or ambulatory settings, not on population testing needs in a pandemic.
Typically, diagnostic laboratories are connected electronically to units within hospitals and to particular ambulatory clients but rarely farther afield to public health units or regional governments. While the communications technology is feasible today, barriers to better interconnectivity range from presence of multiple, insufficiently standardized informatics systems in labs, public health units and regions, privacy protection concerns, to debates about which payor should bear connection costs. An option to develop low-cost connectivity is to bypass legacy specialized systems and their attendant bureaucracies by using encrypted cell phones directly attached to point-of care-diagnostics devices and to public health units.
Further, the COVID-19 pandemic is a prime example where a vast mountain of molecular diagnostics-associated data has been collected, far too much to be analyzed and used most effectively in a timely manner by conventional means. The opportunity presents opportunities, first to revisit this data using artificial intelligence to discern useful patterns for early detection and assessment of COVID-19, and then to embed the algorithms into future public health informatics systems.
What are the lessons to be learned from molecular diagnostics experience with COVID-19?It has been demonstrated that sensitive and specific molecular diagnostics tests for applications, such as new pathogens, can be fabricated within months. However, to be maximally effective the tests must be deployed in systems that facilitate analysis and dissemination of results, rapidly, to a wide range of decision makers. This implies that the information systems must be simplified and integrated; the seams in the system must be reduced drastically. The COVID-19 experience has shown clearly what is needed: molecular diagnostics at point-of-care, with results reporting on the same visit, simultaneous export of anonymized results to public health agencies and governments, and Artificial Intelligence techniques to assist analysis and interpretation of test results.
COVID-19 has shown that more sensitive and specific tests to assess inflammation, immune reactions, and response to treatment are needed. Most interestingly, the laboratory and informatics components to meet these needs are now available as is the cost/benefit business case in terms of population health. What is needed is a consensus that lab diagnostic systems must be built now, not only to serve individuals but also to support local and distant populations.
The dividend from the COVID-19 experience will be future investment in molecular diagnostics. This investment promises to better knowledge of infectious disease prevalence as well to yield novel molecular technology and specific tests for better diagnosis and control of various conditions extending well beyond infectious diseases.
The pandemic has demonstrated the need for rapid molecular diagnostics, adequately and equitably distributed and the need for lab informatics connectivity and data analysis capability at least an order of magnitude better than what exists today. The response to COVID-19 has increased molecular diagnostics capacity, equitable access to diagnostics, and better lab informatics systems are recognized. Remaining needs include the build out of better information systems, ongoing molecular diagnostics research to shorten test development times, shorten analytical test times, and make molecular diagnostics tests more reliable.
However, the paramount need is to ensure that locally, nationally, and internationally, molecular diagnostics capacity and momentum for advancement is maintained.
Diagnostic-test manufacturers are playing a critical role in government efforts to respond to the COVID-19 pandemic. Yet, their work to increase the IVD supply is also initiating changes in the industry that could lead not only to greater adoption but also to greater competition. Much more than the course of the pandemic is uncertain. What role will PoC diagnostics play in the delivery of care? How will the supply landscape for reagents evolve? Will emerging alternative and complementary technologies and platforms have a major impact on the testing landscape and if so, when? How will regulators respond to the high demand for tests? Will they authorize at-home molecular tests?
These are some of the important questions that IVD-test manufacturers need to consider as they strategize to position themselves for long-term success. For although the precise nature of the future for the IVD industry is unclear, it is clear that change is afoot. Companies would be wise to prepare.
