January 1, 1970 (Vol. , No. )
Bori Shushan, Ph.D.
Liquid chromatography-mass spectrometry is great in research settings, but can it help in your hospital lab? This author says yes.
The sheer power and accuracy of liquid chromatography-mass spectrometry (LC-MS/MS) is undeniable. It has earned a reputation as the analytical “gold standard,” delivering high quality and specificity, particularly for small molecule analytes including drugs of abuse, therapeutic drugs, immunosuppressants, steroids, and vitamin D metabolites. A growing number of hospital laboratories are starting to consider the value it can bring to them not in the distant future, but now. By offering the benefits of time savings, cost savings, and improved patient care, LC-MS/MS could be one of the clinical laboratory’s most important improvements in decades.
While the trend toward the clinical adoption of LC-MS/MS is gaining momentum, only approximately five percent of LC-MS/MS instruments are actually used in the clinical lab today. The rest are in research settings, academic institutions, or reference labs. The clinical laboratory then presents a leadership opportunity for people in the in vitro diagnostics industry who can apply real innovation to current practices.
The Cost of High Quality
All laboratories seek to provide an accurate result to support the physician’s role in treating patients effectively. LC-MS/MS is an excellent option to deliver high quality; however, the issue is complexity.
The current generation of LC-MS/MS solutions requires highly trained operators, forcing most clinical laboratories to use traditional methods such as immunoassays. Another option includes sending out tests to reference laboratories that are equipped with LC-MS/MS technology; however, there are trade-offs with this practice. Send-out testing is expensive and it requires the clinician to wait longer for a test result. This alternative is becoming less viable due to the growing number of people gaining access to healthcare and a general increase in testing volumes. Notable examples include the global testing market for vitamin D tests, which is expected to grow at a compound annual growth rate of 33.5 percent through 2014.1 Also, the rise in use and abuse of opiate/opioid drugs for pain management is also putting pressure on clinical laboratories to provide high-quality services in this area.2
“We’re spending $500,000 a year on tests we send out to reference labs,” says Amin Mohammad, Ph.D., a pathology professor at the Texas A&M University System Health Science Center and Medical Director of Laboratory Information System at the affiliated Scott & White Health Care System. “This burden has grown quickly over the past few years because of the intensified focus on better pain management and the parallel problem of drug abuse. Having LC-MS/MS in our laboratory could reduce our costs dramatically and also reduce the very real possibility of sample loss or mix-up. We would recoup our investment in one and a half years while improving patient care.”
Cost concerns are putting pressure on clinics in Europe as well. “We’re expected to do more with less,” says Pierre Marquet, head of the department of pharmacology-toxicology, University Hospital of Limoges, France. Like other parts of the world, France has weathered a recent recession that saw taxes rise and government workforces shrink. “We try to integrate and automate as much as possible the different aspects of our lab workflow. A more automated, integrated LC-MS/MS system would offer possibilities of 24/7 LC-MS/MS testing by all our technicians or fellows with basic lab tech skills and more affordable salaries.”
Josh Bornhorst, director of chemistry, immunology, point-of-care, and pediatric clinical laboratories, University of Arkansas states, “Turnaround time is also a major factor for labs, and time is lost when samples go out to reference labs for testing. We now have to send out drugs of abuse confirmations, but we could do them in house with mass spectrometry.” He estimates that LC-MS/MS at the university medical center could reduce turnaround times from two to four days for outsourced tests to a matter of hours for in-house tests. “That would improve patient care,” says Bornhorst.
Adds Mohammad, “By reducing our turnaround time from 10 days to as little as an hour with in-house LC-MS/MS, we would improve our service to physicians, meaning better patient care, whether a patient needs medication or addiction counseling.”
Challenges with Specialized Testing
Immunoassays are the primary method for specialty diagnostics in clinical hospital laboratories. They can be run at high throughput on automated analyzers but have quality drawbacks due to cross-reactivity and interferences of closely related compounds such as metabolites of other drugs with similar core structures. LC-MS/MS technology is different. It separates analytes chromatographically then ionizes molecules to further separate them by mass-to-charge ratio and directly measures the concentration of a particular analyte. Immunoassay manufacturers are limited to assays where a suitable antibody can be developed. LC-MS/MS, however, does not have this constraint, since it does not require antibodies in the method formulation. Because of this, the potential for menu growth either by the laboratory (via lab developed tests) or the manufacturer (via vendor developed tests) is significant.
LC-MS/MS also overcomes the issue of waste. If you don’t use all 100 tests in an immunoassay kit before it expires, the rest must be thrown away. LC-MS/MS, by contrast, is “reagent-less,” using primarily an internal standard, which is stable for longer periods of time and is used in small quantities. Laboratories can also run panels of tests with just a small amount of patient sample and internal standard, which improves the yield vs. immunoassay kits. This can have a positive impact on the finances of the lab, potentially lowering the costs on a per test basis.
“For us, LC-MS/MS offers two big advantages,” says Sally Benton, consultant biochemist at the Royal London Hospital, which operates two maxed-out LC-MS devices and is considering a third. “The first is quality of result—that is, eliminating the interferences in immunoassay that can lead to misleading vitamin D and testosterone results. The other is cost-effectiveness, with operating costs around one-fifth that of immunoassay. Cost is a major factor in the United Kingdom as it is elsewhere. Saving money and improving quality are paramount.”
Quality of result is definitely driving LC-MS/MS demand from the clinician perspective. “The quality difference between immunoassay and mass spectrometry is huge,” says Torsten Binscheck, head of toxicology and laboratory medicine at Labor Berlin Laboratory in Germany. “There’s immense pressure on the market. Clinicians are coming to us because they want higher quality test results.”
Still Too Complicated
Unfortunately, only highly skilled specialists can make use of the current research-class LC-MS/MS instruments used today. The problem starts with developing and validating assay methods in the first place—a task which can take up to six months or more to complete.
“The diagnostics vendors haven’t yet caught up to the market need,” says Mohammad. “My lab does eight million tests per year. For us to bring up assays in a hospital setting, they need to be well developed in the form of a kit where we place the reagent on a particular analyzer, load the samples, calibrate the machines and get the result out.”
Mohammed is not alone. Hospitals have a strong preference for ready-made methods, shifting the risk away from the laboratory and to the vendor. In addition, each test, as well as the system itself, should be approved by the appropriate regulatory authorities for routine clinical use (i.e., FDA 510k, or CE/IVD mark). That’s not how it is with today’s generation of LC-MS/MS instruments.
“Today, the lab itself has to do the methodology development,” Mohammad says. “The industry will sell us the machine, but we must find by ourselves the vendors who can sell us the standards, calibrators, and then the controls. Often, laboratories need to make their own calibrators and controls. Next we have to figure out the metrics and perform stability testing to determine when a calibrator starts going bad. Many laboratories like mine don’t want to get involved in all of this. It’s a lot of paperwork and administrative work. When we get inspected, all of this documentation needs to be shown to the inspecting agency to prove we are doing our job properly. That’s why these techniques have never been taken up in the hospital laboratory.”
The question is how to get LC-MS/MS in the laboratory in a less intimidating, more cost-conscious way that supports standard clinical lab workflow. “At last,” says Mohammad, “the dynamics are actually changing.”
What the Ultimate Solution Looks Like
We’re on the cusp of a breakthrough in specialty diagnostic testing, close to having LC-MS/MS in many different types and sizes of hospital laboratories. Ideally, the new technology will offer a fully integrated and automated system that includes FDA cleared and/or CE-IVD marked methods, software, accessories, consumables, along with reliable service and support.
The analyzers should look and behave like the ones that current laboratory technologists already use in the clinical hospital environment and are confident with operating. If the new technology passes muster, it holds the potential for true transformation of the clinical laboratory by providing highly specific and accurate testing in a random access format that is easy to use, reducing sample transport costs, saving significant time, and freeing capacity in central labs to develop new high-margin esoteric assays. “For a laboratory that already uses LC-MS/MS analyzers, it would also eliminate the need for batching, allowing random access workflow that would get doctors and patients answers more quickly,” notes Royal London Hospital’s Benton. Furthermore it can free up the capacity of open LC-MS/MS instruments to develop new high-margin esoteric methods and offer expanded services to physicians with a competitive menu.
In addition to these benefits, the ideal automated LC-MS/MS solution offers possibilities for a rapid expansion of assays. “If it’s a commercial diagnostic, you have to think about development time,” says William Clarke, Ph.D., associate professor of pathology/director of point-of-care testing and TDM/toxicology at Johns Hopkins. “Most commercial immunoassays take two to five years to develop from the point when a clinical need is identified. If you have a mass spectrometry-based platform, you’ll be able to do that in months rather than years. Once the clinical need is identified, particularly with small molecules, you’ll be able to ramp up quickly and get a product for submission and hopefully FDA clearance in a much shorter time frame. That’s a decided advantage.”
Other Market Needs
Although the benefits of LC-MS/MS are tempting, there are further kinks that need to be worked out before it’s a reality.
“Analyzers should fully integrate with laboratory information systems (LIS) and laboratory automation systems in a bidirectional way,” says Marquet. “Operators shouldn’t have to type lists of assays into LC-MS/MS computers or results into the LIS. All of this data should autopopulate, with the devices easily sharing the data they originate.”
Analyzers must also deliver reliable uptime. Suppliers need to provide competent and responsive service teams. It would be a plus if the entire solution and all of its components were manufactured and sourced from a single supplier. Johns Hopkins’ Clarke wants swappable components and the ability to handle the dirtier samples of a clinical lab. “We take care of patients 24/7,” he says. “We can’t be constantly breaking down the machine to clean it or waiting for service.”
With these requirements covered, LC-MS/MS’s potential value will only grow as new biomarkers are discovered. Mohammad sees its increasing applicability to a wide range of low-volume esoteric assays, such as those to diagnose conditions in newborns and young children. Examples include organic acidurias, amino acidurias, and congenital adrenal hyperplasia. He also sees applicability to the therapeutic drug monitoring of new classes of cancer drugs.
“Any lab can give you a result. But what’s becoming more important is customer satisfaction,” says Mohammad. “One customer is the physician and the other is the patient. We need to provide care as quickly and as expeditiously as possible. LC-MS/MS in the clinical laboratory is a powerful tool to advance that mission.”
The need is urgent, says Binscheck. “The demand of the market is high. The company that comes out first with an integrated, automated system will have great success.”
Bori Shushan, Ph.D., is the founder of Clinical Mass Spec Consultants, where he advises industry and institutions in the use of LC-MS/MS with specific emphasis on clinical applications. He is a consultant for Thermo Fisher Scientific.
1 “Global Vitamin D Testing Market 2010–2014,” TechNavio, January 2012.
2 “New advances in pain management screening and confirmation,” MLO Online, last accessed August 1, 2013.