Sophisticated technology dogged by reimbursement woes
BY KAREN APPOLD
Molecular biology is continuing to revolutionize disease diagnosis. Modern molecular tests based on the detection of nucleic acids (ie, DNA and RNA) offer considerable advantages over traditional methods of pathogen detection.
“These procedures can help detect viruses and bacteria more rapidly and with far greater sensitivity and specificity,” says Carole A. Welsch, PhD, MBA, associate director, Personalized Healthcare and Regional Marketing, North America, Qiagen, Germantown, Md.
Other types of molecular tests can help to determine optimal patient therapies, which will improve outcomes and extend the lives of patients with specific genetic makeups. Additionally, these diagnostics can rule out nonresponders and prevent spending millions of dollars on ineffective and potentially harmful therapies, enhancing judicious use of medical care.
“The next-generation sequencing technique is relatively inexpensive, especially when compared to the additional cost of evaluating multiple genes in traditional single-gene tests. It also has a relatively fast turnaround time, an important consideration in patients with advanced disease.”—Wade Samowitz, MD, co-medical director, Molecular Oncology, ARUP Laboratories
Some of the most significant developments in molecular testing in recent years have been related to an increased focus on a personalized health care (PHC) model. “Diagnostic testing is what puts the ‘personalized’ in personalized health care—and molecular diagnostics in particular may play the most prominent role,” says Chris Norris, director of marketing, Molecular Diagnostics, Roche Diagnostics, Indianapolis. “It’s widely accepted today that a PHC model—enabled by high-value diagnostic tests and molecular targeted therapies—will be the key to driving further progress in the treatment of many diseases, particularly cancer.”
The development of molecular markers has also been leveraging increased biological insight, bringing to market potential replacements of historical markers (often proteins) that are typically unspecific. “We are now able to comprehensively look at large collections of genes from both the genetic and epigenetic level,” says Jan Groen, PhD, CEO, MDxHealth, Irvine, Calif. “Many of these novel molecular tests offer direct insight into the biological mechanisms governing a disease, resulting in targeted diagnostics and therapies.” Several novel screening methods are also being developed that use the increased understanding of underlying biology.
James Coull, PhD, chief technology officer, AdvanDx Inc, Woburn, Mass, sees a trend toward faster, simpler assays, which can be performed using less sophisticated, and in some cases, portable instrumentation. “This is happening across a broad range of molecular technologies, including polymerase chain reaction (PCR) and various target amplification methods, as well as fluorescence in situ hybridization (FISH),” he says.
|“It’s widely accepted today that a PHC [personalized health care] model—enabled by high-value diagnostic tests and molecular targeted therapies—will be the key to driving further progress in the treatment of many diseases, particularly cancer.”—Chris Norris, director of marketing, Molecular Diagnostics, Roche Diagnostics
On the Horizon
Molecular testing is an ever-expanding reality. The FDA has already identified various diagnostic biomarkers for more than 100 existing drugs that target a variety of diseases, and has approved 15 companion diagnostics.
“Detecting particular mutations in oncogenes such as KRAS, PI3K, EGFR, JAK2, or BRAF will give us the ability to predict how patients suffering from various malignancies respond to different therapies,” Welsch says. “In the long term, not only are we changing the course of treatment for patients, but we are also building the clinical understanding for designing new targeted cancer treatments in the future. And PCR and Sanger sequencing are just the beginning, with next-generation sequencing opportunities for diagnostics developing quickly.
|“In the long term, not only are we changing the course of treatment for patients, but we are also building the clinical understanding for designing new targeted cancer treatments in the future.”—Carole A. Welsch, PhD, MBA, associate director, Personalized Healthcare and Regional Marketing, North America, Qiagen
The technology will gradually move from PCR-based methods to sequencing-based methods, Groen says. The cost for DNA sequencing is decreasing; it’s becoming more robust and better adapted for routine applications. Opportunities are now being created for more integrated disease characterization.
Genomic and epigenomic profiles of a large set of genes, known to be implicated in the onset or progression of cancer or predictive of therapeutic efficacy regardless of their frequency of occurrence, can be determined simultaneously. When multiple technologies are combined (eg, genetics and epigenetics), profiling accuracy can be dramatically increased. From these larger profiles, the most significant information can be extracted, while the remaining information can drive future research, new marker identification, and a more advanced implementation of personalized medicine.
|James Coull, PhD, chief technology officer, AdvanDx Inc, sees a trend toward faster, simpler assays, which can be performed using less sophisticated, and in some cases, portable instrumentation. “This is happening across a broad range of molecular technologies, including polymerase chain reaction (PCR) and various target amplification methods, as well as fluorescence in situ hybridization (FISH),” he says.
In addition to the current capability to detect point mutations across numerous genes in a single assay, ARUP Laboratories, Salt Lake City, is working toward future iterations of testing that will include detection of translocations and copy number variation. “These are important in the pathology of cancer, and the ability to detect them in a single platform with somatic point mutations would be a significant addition to patient care,” says Cecily P. Vaughn, MS, senior scientist, ARUP Institute for Clinical and Experimental Pathology.
In terms of test development, Norris expects the trend of pharmaceuticals being developed with a companion diagnostic to continue, especially in the area of oncology. “This targeted therapy approach provides significant clinical benefits, most notably greater treatment efficacy,” he says. “Therefore, it helps to reduce the overall costs of health care because you improve outcomes for the targeted population and help prevent some of the potential adverse outcomes that can result from the ‘one size fits all’ approach to therapy.”
Today’s molecular diagnostic testing products offer many innovative features that benefit laboratories when performing patient testing. Some of the newer offerings on the market are shown below.
The 3500 Dx/3500xL Dx CS2 Genetic Analyzers from Life Technologies’ Applied Biosystems™, Carlsbad, Calif, Invitrogen SeCore® HLA Sequencing Kits, and uTYPE® Dx HLA Sequence Analysis Software, constitute the first FDA 510(k)-cleared, sequence-based system for HLA typing in the United States. “With clearance of this system, transplant patients can now have the confidence that their HLA tissue typing was performed utilizing a thoroughly tested, high-resolution technique that has passed the strict test requirements of the FDA,” says Ronnie Andrews, president of medical sciences, Life Technologies, Carlsbad, Calif. “Precise HLA matching between donor and patient significantly improves overall transplant survival.” HLA typing on the 3500 Dx offers labs an optimized, streamlined workflow with higher resolution than other molecular HLA typing technologies such as sequence-specific oligonucleotide methods.
Life Technologies’ QuantStudio™ Dx is also FDA 510(k) cleared for use, specifically with the Quidel Molecular Direct C. difficile assay. The instrument’s flexibility is enabled through an optional test development mode, allowing for easily interchangeable thermal cycling blocks that accommodate 96- or 384-well plates and a proprietary qPCR microfluidics card, which can perform 48 tests on eight samples simultaneously without the need for liquid-handling robots. The card can also be used to design and implement custom tests. The QuantStudio Dx can perform numerous functions, including pathogen detection, gene-expression analysis, SNP genotyping, copy number analysis, mutation detection, micro-RNA, and other non-coding RNA analysis, as well as high-resolution melt analysis.
The [removed]ColonSentry[/removed]® from GeneNews Limited, Toronto, is a blood test that measures the expression of seven genes, which serve as biomarkers to detect colon cancer risk. “The science behind the ColonSentry test is based on the Sentinel Principle®, an approach that identifies biomarkers for disease in circulating blood to detect what is occurring throughout your body,” says Gailina Liew, LLB, MBA, president and COO. No stool samples or dietary restrictions are necessary.
An offering by MDxHealth, Irvine, Calif, ConfirmMDx™ for prostate cancer, is an epigenetic assay that helps urologists distinguish between patients who have a true-negative biopsy from those at risk for occult cancer. “The test helps urologists rule out prostate cancer-free men from undergoing unnecessary repeat biopsies, and helps rule in high-risk patients who may require repeat biopsies and potential treatment,” Groen says. The ConfirmMDx test is able to detect an epigenetic field effect or “halo” associated with the cancerization process at the DNA level. With a negative ConfirmMDx result, which provides a 90% negative predictive value, a urologist can avoid a repeat biopsy and manage the patient with routine, noninvasive screening.
MDxHealth’s PredictMDx™ for glioblastoma (glioblastoma multiforme [GBM]) is an epigenetic assay that helps oncologists clinically manage a newly diagnosed GBM patient. The device measures the methylation status of the MGMT gene, which encodes for a DNA repair enzyme. When the gene is methylated, it no longer produces the DNA repair gene. Without the DNA repair gene present, any DNA damage by chemotherapeutic agents is not repaired—so the cell will die. Between 35% and 40% of all newly diagnosed GBM patients will have their MGMT gene methylated. The median overall survival of methylated versus unmethylated patients receiving the standard of care for the disease is 24 months and 16 months, respectively.
ARUP Laboratories’ Solid Tumor Mutation Panel by Next Generation Sequencing allows users to simultaneously test multiple cancer genes for clinically actionable mutations. “The next-generation sequencing technique is relatively inexpensive, especially when compared to the additional cost of evaluating multiple genes in traditional single-gene tests,” says Wade Samowitz, MD, co-medical director, Molecular Oncology, ARUP Laboratories. “It also has a relatively fast turnaround time, an important consideration in patients with advanced disease.” Finally, mutations in genes that would usually not be considered relevant for a particular tumor can be identified, allowing for novel interventions.
The therascreen® EGFR RGQ PCR Kit from QIAGEN, Germantown, Md, enables physicians to identify EGFR mutation-positive patients eligible for treatment with [removed]GILOTRIF[/removed]™ (afatinib). The test was FDA-approved in July. Analytical performance of the therascreen EGFR test has been established for 21 EGFR mutations, including the most prevalent resistance mutation (T790M). The therascreen EGFR test can detect EGFR mutations in separate tubes.
The therascreen KRAS RGQ PCR Kit is a genetic test designed to detect the presence of mutations in the K-ras gene in colorectal cancer cells. This test is the only FDA-approved KRAS companion diagnostic test currently on the market. “It gives health care providers a fast, consistent, and reliable process to determine optimal treatment for colorectal cancer patients who are candidates for EGFR-inhibitor therapy,” Welsch says. The therascreen KRAS kit has been shown to have higher sensitivity (ie, a lower limit of detection) for KRAS mutations between 0.8% and 6.4%, depending on the assay. The therascreen KRAS test offers labs an efficient workflow based on the Rotor-Gene Q MDx, an automated molecular detection instrument that uses real-time PCR technology.
Using FISH technology, AdvanDx has developed rapid molecular tests that detect blood-borne pathogens that cause bloodstream infections (that can lead to sepsis and death). By identifying the causative pathogen, clinicians can prescribe more effective treatments, leading to a greater likelihood of survival and cost savings. AdvanDx has developed a panel of highly accurate, 20-minute QuickFISH™ tests that identify the majority of pathogens responsible for bloodstream infections. “Because the tests are so rapid, results can be bundled and provided with other critical laboratory information, such as the gram stain result, to provide a great amount of actionable information,” Coull says.
AdvanDx is also developing a rapid method detection of methicillin resistance in Staphylococcus aureus (ie, MRSA). “This new test measures whether a functional mecA gene is present in the organism, which correlates very highly with the MRSA phenotype,” Coull says. “Whereas many assays only detect the presence of the mecA gene, for example by PCR, the AdvanDx test measures whether the gene is able to actively produce mRNA. Therefore, we expect that our test will have fewer false-positive results than gene-amplification tests when compared to actual resistance
In May, the FDA approved the cobas EGFR Mutation Test, from Roche Molecular Diagnostics, Pleasanton, Calif, a companion diagnostic for the cancer drug Tarceva (erlotinib). “This was the first FDA-approved companion diagnostic that detects epidermal growth factor receptor (EGFR) gene mutations, which are present in approximately 10% of non-small cell lung cancers (NSCLC),” Norris says. The test was approved with an expanded use for Tarceva as a first-line treatment for patients with NSCLC that has metastasized and who have certain EGFR gene mutations.
The FDA has also approved Roche Molecular Diagnostics’ next-generation viral load test to manage patients with chronic hepatitis C virus infection. A real-time PCR-based test, the COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 provides a novel, dual-probe approach for an extra layer of protection in detecting and quantifying the virus. “The test is designed to accurately determine the amount of hepatitis C virus RNA in order to assess a patient’s response to antiviral therapy,” Norris says.
Low Pricing for Diagnostic Codes Could Bring a Host of Negative Consequences
The Medicare Administrative Contractors (MAC) released 2013 pricing for dozens of new molecular diagnostic tests, including tests that help to determine effective cancer therapies for patients. Immediate analyses indicate that some of the new codes are priced far below the cost of an FDA-cleared companion diagnostic testing kit, leaving other integral cost components unaccounted for. Beyond FDA-cleared companion diagnostics, many lab-developed tests are not being reimbursed at sustainable levels that cover a lab’s costs.
Karen Appold is a contributing writer for CLP. For more information, contact Editor Judy O’Rourke, [email protected].