The Molecular Edge
In a recent public policy paper,1 the Infectious Disease Society of America calls for “Better Tests, Better Care: Improved Diagnostics for Infectious Diseases.” The authors conclude that the need for diagnostics to address unmet needs has never been greater. They also put the onus on diagnostic manufacturers to reduce complexity of testing, enabling walk-away testing.
The past decade has seen the advent of many molecular diagnostic (MDx) tests, including highly integrated, easy to use, cartridge-based sample-to-answer platforms. These more user-friendly sample-to-answer platforms typically offer simple tests for a small number of biomarkers. The most successful test from both a commercial viewpoint and in terms of clinical impact is the MRSA test, in which both the pathogen and its resistance status are detected. Other tests, such as those for C. difficile and TB, among others, are also low-multiplexed, relatively simple assays that deliver narrow and well-defined clinical answers.
However, several medical needs must still be addressed.
First, the need grows for clinically relevant and actionable answers for complex infectious disease, including respiratory tract infections, surgical site infections, prosthetic joint infections, gastrointestinal tract infections, sepsis, and many others. To obtain meaningful diagnostic answers, it is often necessary to detect several dozen-even up to 100-pathogens and their antibiotic resistance markers simultaneously. Such sophisticated diagnostics require highly multiplexed solutions.
Second, the most typical consumers of diagnostic information are clinicians in ICUs without around-the-clock access to sophisticated laboratory resources. Many microbiology labs are staffed only during daytime and have minimal weekend staff, leading to significant delays in obtaining pathogen and resistance information. In the absence of laboratory professionals during night and weekend hours, physicians or nursing staff should be able to operate these sample-to-answer platforms outside of a traditional laboratory environment. However, requiring other medical professionals to conduct this molecular testing is often not feasible without intuitive, easy-to-use platforms. Ideally, such platforms would eliminate operator variability and can be used in just a few minutes with minimal hands-on time.
Third, to fit into routine hospital workflows, ICU- and hospital-based sample-to-answer solutions should be equipped to process any native clinical sample material. However, many existing solutions require either pre-culturing or are usable only with very narrowly defined clinical sample types such as nasal swabs.
Finally, sample-to-answer offerings should combine requirements of an effective walk-away solution: highly-multiplexed assays that work with any native sample type to deliver broad, clinically actionable results in a few hours. Every hour counts in pathogen and resistance detection; mortality rates in indication areas such as sepsis tend to increase by eight percentage points per hour.
Technologically, approaches to some of the unmet needs are as diverse as real-time PCR, MALDI-TOF mass spec, next-generation sequencing and endpoint PCR with microarray-based detection. Suffice it to say, most clinicians are rather indifferent to technology and view these sample-to-answer solutions as black boxes.
Moreover, some of these platforms have become so easy to operate that they decentralize the laboratory, bringing MDx to the patient. Recently, sample-to-answer systems have evolved to enable fully automated lysis of even the most complex native clinical samples. ICUs now have access to these fully enclosed, cartridge-based systems that allow for the detection of 100 or more pathogens and antibiotic resistance markers in 4-5 hours.
However, clinicians, microbiologists, infectiologists and hygienists must closely collaborate to make sense of these new, often complex diagnostic answers. With the help of modern MDx solutions, a new generation of sample-to-answer platforms are being developed that can be operated by literally anyone on a healthcare team. This ease of use will drive clinicians closer to the shared goal of improved infection management.
Clinical adoption is another driver for the adoption of novel sample-to-answer solutions. The higher the degree of multiplexing and the more native clinical sample types, the larger and more complex clinical trials will become to validate such platforms and IVD products. It is quite common to see prospective multicenter clinical trials enrolling several thousand patients to prove the body of evidence to the FDA for clearance of these novel sample-to-answer solutions. Apart from the purely regulatory trials, it is also important to build the health economic case and provide data supporting the medical benefits that accompany savings to the healthcare systems.
With a plethora of novel and innovative sample-to-answer platforms in the pipelines of small and large IVD industry players alike, it will be interesting to observe the consolidation and convergence of platforms around clinically relevant content. Having an offering that addresses truly unmet medical needs and delivers clinically actionable information “has the great potential to make treatment better for the individual and antibiotic stewardship better for the community,” according to David Livermore, PhD, professor of Medical Microbiology at the University of East Anglia.
The delivery of clinically actionable information will grow increasingly important. With the continued proliferation of resistant strains of bacteria, especially multi-drug-resistant Gram-negative bacteria, we are rapidly running out of therapeutic options. A combination of truly novel antibiotics accompanied by a more rational, diagnostics-based selection of antibiotic therapy regimen is urgently needed. Assays and offerings that combine detection of putative pathogens with antibiotic resistance gene detection in a broad and comprehensive manner stand to make the biggest impact on infectious disease diagnosis and treatment in the years to come. Not only will clinicians want to use such sample-to-answer solutions in their treatment regimens, but pharmaceutical companies will also use these platforms in companion diagnostic settings as part of rational patient selection in clinical trials to help develop more targeted and narrow spectrum antibiotics.
The current pressing need for easy-to-use sample-to answer platforms is in infectious diseases. However, it is likely that these platforms will make inroads into oncology, companion diagnostics, genetic testing and many more areas of unmet medical need.
Caliendo AM. Better Tests, Better Care: Improved Diagnostics for Infectious Diseases, CID 2013:57 (Suppl 3) p. 130-170.