“Polymerase chain reaction” and “DNA sequencing” might not be part of the sales rep’s vocabulary today. But the fact is, they probably will be, in the not too distant future.
Molecular diagnostics is ready for prime time.
Take the case of Alere.
In June 2014, the company’s i Influenza A&B moderate complexity molecular test – said to be the only molecular test to detect and differentiate influenza A and B virus in less than 15 minutes – was cleared for marketing by the U.S. Food and Drug Administration. Six months later, in January 2015, the FDA granted the test – which uses a nasal swab sample from the patient – a CLIA waiver.
Three months after that, in April, the FDA cleared for marketing the Alere i Strep A test, said to be the first molecular test that detects Group A Streptococcus bacteria in throat swab specimens in eight minutes or less. Alere subsequently submitted an application for CLIA waiver of the test. Other assays said to be in development on the Alere i platform include respiratory syncytial virus (RSV), C. difficile, and chlamydia/gonorrhea.
Roche offers another example. In November 2014, the company received FDA clearance to market its cobas® Strep A test for the detection of Group A streptococcus bacterial DNA in throat swab specimens. The test runs on the cobas Liat System, a molecular point-of-care diagnostic system, and is said to offer results in 15 minutes.
This isn’t to say there or won’t be a continuing place for other point-of-care diagnostics, such as lower-cost lateral flow tests. But the accuracy of molecular tests as well as the attention being paid to personalized medicine and antibiotic stewardship, could push them into the mainstream, despite some concerns about cost.
“The beauty of molecular tests is that there are very few limitations on what you can do with them,” says Paul Barto, category manager, laboratory, moderately & highly complex testing & instrumentation, McKesson Medical-Surgical. “What we’re seeing right now with point-of-care molecular diagnostics is a focus on infectious disease. When you look at highly complex molecular diagnostics, we have seen lots of advances in oncology and women’s health. Eventually, we’ll see these tests move closer to the patient as well.”
Says lab consultant and speaker Tim Dumas, “This RNA amplification is only limited by our knowledge of a molecule’s DNA structure. As we identify more diseases’ molecular structures, this method will expand and become commonplace. The cost should also come down.”
Targets nucleic acids
Molecular diagnostics is a term used to delineate diagnostic tests that target or detect nucleic acids, that is, RNA or DNA, typically (though not always) following an amplification event, explains Ryan Schmidt, vice president of infectious disease marketing, Alere. “Molecular diagnostics often use a combination of oligonucleotides (often referred to as primers) and enzymes to specifically target and amplify a unique region of a target organism’s genome, with detection of the amplified target region (the product) via labeled probes. These probes detect and often are able to quantify the amount of a target present in the sample being tested.
“The probe is often a labeled nucleic acid – an oligonucleotide – that is complementary to the product being amplified, meaning it can anneal, or bind, to it,” he continues. The label [is] a molecule that emits a signal that can be measured using an instrument with detection capabilities, for example, an instrument that can detect fluorescence, chemiluminescence, voltage, light transmission. In contrast, lateral flow tests are designed to target a protein of some sort, typically an antigen or antibody, without any type of target amplification event.
“The amplification of a target enables lower titers of that target to be detected,” says Schmidt. “This can circumvent some of the problems from poor samples that impact lateral flow performance.”
Barto believes molecular diagnostics typically offer higher test accuracy than other methods. “When you’re doing molecular testing, you’re basically amplifying the sample,” he says. Nasal swabs offer an example.
Lateral flow testing only detects the sample that the provider puts in the analyzer, Barto points out. If the sample is poor, there’s a good chance of misdiagnosis. On the other hand, the molecular test amplifies the sample, for example, influenza, so the provider ends up with a much larger sample size. The result is greater accuracy.
In traditional point-of-care testing, whether it is visually read (strips) or lateral flow, the FDA recommends that, in the case of a negative result for flu during flu season, the provider reflex it, that is, confirm the finding with another test, says Barto. “But if molecular testing is your front-line test, the need to reflex could be eliminated.”
Adds Dumas, “Both lateral flow and molecular (RNA amplication) look for molecules. The molecular test looks for nucleic acid – DNA or RNA – to identify the molecule, while lateral flow uses antibody/antigen response to identify the molecule.
“My analogy would be like identifying a vehicle,” he continues. “Let’s say we are looking for a car, in particular, a red car. The flow test will find the red car and sometimes a car that’s kind of red; and sometimes, it will miss the red car because it didn’t stand out enough. But the molecular test will find the red car and identify its make, model, how many doors, etc. It’s a more accurate test that was, until now, sent to a reference lab for confirmation.”
Closer to the patient
Traditionally, molecular tests – polymerase chain reaction, or PCR, and DNA sequencing – were run in the reference lab. “These are large instruments, highly complex, geared toward high throughput,” says Barto. But, as with so many laboratory tests, the technology is moving closer and closer to the patient in the doctor’s office. And that trend will continue, he predicts. For example, the BRCA1&2 tests, which can indicate a predisposition to female breast and ovarian cancer, are still highly complex, expensive tests. But it’s not out of the question that even these will find their way to the primary care office in the future.
“In the last 10 years, [molecular analyzers] have come down in size, and the level of complexity has come down as well,” he continues. “The goal for any point-of-care test is to get an answer while the patient is in the office. Molecular tests tend to have a slightly longer process time, because of the nature of the technology. But the goal is to get that process time [shorter]. It’s getting closer.”
Some believe that molecular testing will help providers address two issues of importance to the healthcare community today – antibiotic resistance, and the need to “personalize” medicine in an effort to improve outcomes and reduce waste.
“There is a clear tie-in to antibiotic stewardship,” says Rick Graham, senior director, lab category management, McKesson Medical-Surgical. That’s important, as the Centers for Disease Control and Prevention as well as the Obama Administration have targeted antibiotic resistance as a major healthcare threat.
Because molecular tests tend to eliminate the need to reflex a negative result for an infectious disease, such as flu or strep, Graham says the patient can leave the doctor’s office with a definitive answer to the question, “Do I need a prescription or not?” Compare that to the situation that often unfolds today, where the doctor writes the prescription but tells the patient to hold off filling it for a couple of days, until the confirmatory test results come back. “What often happens is, the patient gets it filled anyway right after the appointment,” he points out.
Meanwhile, molecular testing dovetails with the healthcare community’s interest in so-called “personalized medicine,” according to those with whom Repertoire spoke.
“Personalized medicine is about treating each individual for just what they need,” says Dumas. “No more testing to rule out things that are possible but not probable. Providers are going to be judged on pinpointing a diagnosis and performing tests to verify their suspicions. More accurate lab tests will prevail in this new market.”
Says Schmidt, “Personalized medicine refers to understanding each individual’s genetic makeup and taking advantage of that knowledge to treat each individual uniquely based on this knowledge. Molecular diagnostics is and will play a huge role in personalized medicine, and they are often thought of hand in hand.”
Barto points out the role of molecular testing in helping doctors and patients predict the effectiveness of a prescription drug. Case in point: Plavix (generic name clopidogrel), an anti-blood-clotting medication. The U.S. Food and Drug Administration called for a warning on the drug’s label alerting providers and patients that patients who cannot effectively metabolize the drug may not receive the full benefits from it. Providers are advised that tests are available to identify genetic differences in the function of liver enzymes, which determine the patient’s ability to metabolize.
Research is also being done on chemotherapy drugs and certain pain medications, in an effort to determine how metabolic pathways affect patients’ response to them, according to Barto and Graham. Molecular testing is part of that research.
Molecular testing faces some hurdles to widespread implementation in the physician’s office. The first is the time it takes for such tests to yield results. The second is cost.
As the technology matures, time is less and less a factor, says Schmidt. Traditionally, molecular tests could take as long as 75 to 90 minutes to yield results. “But the new point-of-care molecular testing platforms are capable of delivering results in a matter of minutes,” he says. “These are CLIA-waived systems, and as such, they can generate results in 15 to 20 minutes by a diverse set of users. Many lateral flow assays are also CLIA-waived, and generate results in similar time frames.”
The total run time for the Alere i Strep A test is eight minutes, with a few minutes of hands-on time, he points out. “This is very similar to current lateral flow tests. The true value of the POC CLIA-waived molecular systems is that they can deliver the improved result in a timeframe that allows the healthcare professional to make the appropriate treatment decision.”
That said, the larger issue might be price. But even that shouldn’t be a deal-breaker, according to those with whom Repertoire spoke.
“Molecular diagnostics are more expensive than lateral flow tests, but are more likely to give a one-and-done result, offer increased case yield, and potentially reduce the need for send out/confirmatory testing,” says Schmidt. Medicare, Medicaid and private payers reimburse for molecular diagnostics with specific CPT codes, he adds.
Says Dumas, in order for molecular testing to take hold, physicians need to see the value of getting an accurate result and avoiding the time and expense associated with prescribing antibiotics unnecessarily or letting an undiagnosed influenza spread. “In an era of value-based medicine, if insurance companies are serious about paying based on value, then the molecular test is a better value for the money.” And, as with any test, the cost of molecular testing will decrease as the technology becomes more commonplace.
“I think there will be a balance, where lateral flow can be used as a screen, and molecular for confirmation, says Dumas. “Some providers may want to do that, others will go direct to the molecular.”
Molecular diagnostic tests are being developed for a variety of diseases/conditions, including infectious disease (influenza, strep A, RSV, chlamydia/gonorrhea, Clostridium difficile, HPV, TB, HIV, etc.) and companion diagnostics (for example, to evaluate a biopsy for the presence of cancerous cells carrying specific gene mutations), says Schmidt. Molecular diagnostics are also being used in the fields of food safety, agriculture testing, veterinary testing, GMO testing, etc.
For the distributor rep, the sale is simple, he adds. “Unparalleled sensitivity equals better outcomes for the patient, physician, community and healthcare.”