Determining the precise molecular structure of DNA was not only the launching point of what would become the field of modern molecular biology, but it also led scientists to avant-garde thinking about how to detect and ultimately treat disease. These novel concepts would quickly develop into a clinical reality that has been deeply ingrained in elucidating the underlying mechanisms regulating gene and protein expression, in concordance with the overall function of these biomolecules for normal and pathological states.

Molecular diagnostics began as reagents and methodology to identify genetic markers that, research groups postulated, controlled various diseases. For instance, as early as 1949, Linus Pauling and his colleagues had already introduced the term “molecular disease” into the scientific lexicon to describe the changes they observed—that a single amino acid substitution was responsible for molecular changes in hemoglobin leading to sickle cell disease. This arguably constitutes the earliest example of molecular diagnostic development, which set the framework for the field to explode about 30 years later, when researchers performed the first prenatal genetic test for Thalassemia. The scientists utilized a newly developed method called restriction fragment length polymorphism (RFLP), to hunt down the mutant allele from fetal fibroblast cells.

Soon after the use of this genetic test to predict disease, the burgeoning discipline of molecular biology blossomed into a full-on technological boom—much of which can be attributed to the game-changing DNA amplification technique, PCR that was first detailed in the literature in 1985. Two years later PerkinElmer launched its first PCR thermocycler, a ubiquitous piece of equipment essential to every molecular biology laboratory, and with that, the molecular diagnostic equipment market set off down a path that is still on the rise and shows no sign of slowing down.

Now, in the post-genomic era, molecular diagnostics have not only aided scientists toward a better understanding of how our genetic code operates to coordinate daily metabolic functions, but are also becoming essential clinical tools that physicians use to identify, diagnose, and track disease. However, the foray of clinical diagnostics into genomic medicine is not as straightforward as it was adapting them to the laboratory environment.

Trials and Tribulations

To facilitate the commercialization of molecular diagnostic products, companies need to consider several fundamental factors and overcome critical issues that could limit widespread adoption. Beyond the obvious license or ownership of the intellectual property required for the core technology, it is essential for diagnostic developers to consider the overall goal of what they intend the product to achieve. Will the test or device aid a physician to accurately diagnose patients and prescribe an appropriate therapy?

During the development phase, companies work out the ideal set of characteristics to embody their new product to attract users. Ideally, new molecular diagnostics need to be rapid, sensitive, have high specificity, and be cost effective. Additional qualities such as ease of use and adaptability are increasingly becoming more important to end users. These qualities then get added to the growing list of parameters that developers try to meet for their new product, ultimately having to prioritize which asset is most important to the overall product goal.

Once research and development teams feel the final product is ready for clinical use, a new set of regulations falls into place. At this point, companies have a few more decisions to make that will affect the product usage and possible performance in the commercialized markets.

“The first major hurdle would be regulation and the decision of whether to release the product as laboratory developed test (LDT) or as an FDA-cleared in vitro diagnostic (IVD),” explained Shawn Baker, Ph.D., co-founder and CSO of AllSeq, a genomics business consultancy and creator of the Sequencing Marketplace. “The LDT path is much simpler, but the FDA has signaled that they should have more oversight and that most diagnostics should go through clinical trials. That obviously takes a lot of time and resources, leading the Centers for Medicare & Medicaid Services (CMS, which regulates the CLIA environment under which LDTs are developed) to argue that over-regulation will prevent many diagnostic tests from ever being brought to market.”

“The second major risk is that of reimbursement,” Dr. Baker added. “Just bringing a diagnostic to market doesn’t ensure that it will be financially viable, insurance companies have to agree to pay for it.”

Tadd Lazarus, M.D., chief medical officer at Qiagen agreed with Dr. Baker’s assessment, adding that “reimbursement levels for new diagnostics are often based on technical aspects of the diagnostic method and don’t necessarily reflect the clinical value of a test. Insurance companies are often asking for hard health economic evidence, which requires additional evidence beyond what is already being required by regulatory authorities.”

Dr. Lazarus continued stating “opposing interests in the health care and political systems delay decisions regarding best practice and reimbursement—and thus the introduction of innovations. Often, the lag in reimbursement policies and systems encourages the treatment of diseases rather than their prevention through the early use of diagnostics.”

In addition to LDTs and IVDs, analyte specific reagents, which the FDA defines as “antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reactions with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.” These compounds are most often sold to IVD manufacturers, CLIA laboratories, as well as nonclinical laboratories, and add dimension to the commercialization process, since they are regulated by the FDA and typically classified as Class I medical devices—which makes them subject to a host of regulations and restrictions.

“Historically it’s been difficult to apply value-based pricing on diagnostic assays (e.g., higher prices for assays that satisfy an unmet need or save on other costs), Dr. Baker stated.  “Instead, they are often priced (by the payors) using a variant of a ‘cost-plus’ model—vendors are reimbursed for the cost of running the assay plus some overhead for profit. This is in contrast to pharmaceuticals, which are usually priced more according to market demand or based on value added (e.g., change in quality of life, time of life extension, etc.)”

Shaping Clinical Medicine

Regulatory and reimbursement issues notwithstanding, molecular diagnostics have already begun to have an effect on how clinical medicine is practiced, mostly in positive ways. With continued declines in cost, due to advances in next-generation sequencing, the price per genome value has allowed for the democratization of genomic medicine, opening up research avenues to an increasingly larger number of investigators. All of these new studies have allowed scientists to identify considerably more actionable biomarkers that assist physicians in identifying disease early and provides valuable treatment insight, such as drug therapy resistance due to a specific genetic background.

“Technological innovation is driving the speed and performance of molecular diagnostics, and a future in which sequencing is being routinely performed is very close,” Dr. Lazarus remarked.

“We already see a big impact in two areas,” Dr. Baker noted, “The first is non-invasive prenatal testing (NIPT), which is rapidly replacing older, more invasive methods of testing for fetal genetic anomalies. The other area is in cancer where molecular diagnostics can offer a more comprehensive view of the underlying diseases of the genome.”

One of the most exciting and promising molecular diagnostic breakthroughs in the past several years has come from advances in liquid biopsy. The ability to capture and detect minuscule amounts of circulating DNA from pathological sources such as cancer cells is poised to have a clinically meaningful impact for disease prognostication.

“Liquid biopsies hold great promise for monitoring of disease progression and detection of resistance mutations—this cannot be reasonably achieved with invasive, burdensome tissue biopsies,” stated Qiagen.

Dr. Baker agreed and added that “similar to what’s been done with NIPT; cancer diagnostics are moving into the liquid biopsy space—monitoring the blood for cancer signals rather than directly biopsying the tumor.”

Clinical Transition Horizons

Looking toward the future, it is hard not to imagine the significant impact that molecular diagnostic products will have in clinical medicine. The full potential of precision medicine will be fulfilled once a number of these molecular products have fully transitioned from add-on assays to complete point-of-care diagnostics that replace traditional techniques and are used on a regular basis.

“There may be a move from companion diagnostics to companion pharmaceuticals,” Dr. Baker said. “That is, rather than having a drug in mind for a patient and running a diagnostic to see if it’s the right drug or picking the right dosage, a comprehensive diagnostic (or diagnostic panel) would be run which would determine which drug or drug combination is right for the patient.” Which in the end, tailored patient care is the foundation of the personalized medicine philosophy.

 

This article was originally published in the April 2016 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.

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