Until recently, molecular diagnostics methods were labor-intensive, expensive processes that required highly knowledgeable and expert scientists with specific experience. The information had vast potential, but it seemed there was a need for more to really obtain value.

Enter the human genome project. Its goals demanded improvements in testing methods, and researchers responded, surpassing the objectives with amazing speed. Sequencing methods improved, and the genome was mapped. Some of the data yielded information with clinical relevance.

Large academic and research hospitals began integrating molecular testing methods into their clinical labs. Advances in processes and menus continued. New molecular diagnostic methods became faster and less complex. Many established high clinical utility, and many others, such as genomics, continue to hold great promise. Some of these tests have even been commercialized, automated, and made financially obtainable.

It’s no wonder, then, that the field is one of the fastest-growing segments of in vitro diagnostics. Before bringing molecular diagnostics in-house, clinical labs need to determine how they will deal with the variety of factors that will impact the success of the venture: value, architecture, testing menus and methods, automation, laboratory-developed assays, physician education, and reimbursement.

 

Is It Worth It?
“There is a strong interest in the marketplace for molecular diagnostics, and there are good examples of when it’s a better clinical practice than the current standard,” says Bob Proulx, VP of marketing for Nanogen Inc in San Diego. This might mean a faster turnaround or a less invasive sample collection, for example.

“The information a molecular assay can give to the physician can help to determine the diagnosis and course of treatment,” Proulx says. The sooner that information is delivered, the better. “Real-time PCR can deliver a result in less than a day, versus 3 to 7 days for a viral culture or even longer for some targets,” he says.

If not time, then molecular tests should provide some other advantage. “Physicians wanting to test for herpes simplex encephalitis (HSE) used to have to do a brain biopsy to gather a sample. Now, with molecular methods, they need only collect cerebral spinal fluid, significantly changing the patient experience,” Proulx says.

Elaine Lyon, PhD

“Molecular diagnostics should complement traditional testing and, when appropriate, can replace it,” says Elaine Lyon, PhD, chair of the Association for Molecular Pathology (AMP) clinical practice committee; assistant professor at the University of Utah (Salt Lake City); and medical director of molecular genetics, ARUP Laboratories Inc in Salt Lake City.

Lyon uses fragile X as an example. “The test used to be done by cytogenetics, but the sensitivity was low. The standard now for fragile X testing is the molecular assay,” she says.

However, before bringing a test in-house, Proulx advocates considering the feasibility, cost, and appropriateness. “In some cases, the volume may not justify the expense. The question then becomes, ‘Should the lab offer molecular diagnostics even if they are outsourced?’ ” Proulx asks.

Craig Hill, PhD, manager of scientific affairs for Gen-Probe Inc in San Diego, thinks they should. “Every clinical lab should at least use the FDA-cleared tests,” he says, citing those for chlamydia, gonorrhea, HIV, hepatitis C, and human papillomavirus (HPV). “For these tests, the volume is certainly there for most labs,” Hill adds.

The Setup
Once the decision to bring molecular diagnostics in-house is made, a facility must determine whether the tests will be centralized in one molecular diagnostic lab or decentralized throughout all of the clinical labs. Many labs have found that the lab starts out centralized, but becomes decentralized because of the wide variety of tests in all areas.

“Our molecular diagnostics started out with a centralized architecture, but as the number of tests grew, it made more sense to group them into the disciplines,” Lyon says. She acknowledges, however, that automation may encourage centralization, while differing methods of testing may push for a decentralized architecture.

“There are different needs for infectious-disease testing, hematopathology, and genetics. It’s difficult to find procedures or automation that work for all three,” Lyon says.

What’s on the Menu?
Of course, if bringing in just a few tests, the issue of architecture may not be a bothersome one. Which tests to use depends on which are needed as well as their clinical utility.

Craig Hill, PhD

According to Hill, tests whose use is steadily increasing include chlamydia and gonorrhea assays, HIV, and HPV. Mike Sullivan, CEO and co-founder of Centice Corp in Durham, NC, suggests there are always areas of applications for infectious diseases and nucleic acid testing, particularly for clinical labs, high-throughout screening, and drug discovery. “We can detect different flu strains and perform blood analysis. Even clinical chemistry can be more efficient with molecular diagnostics,” Sullivan says.

“The nature of molecular testing in labs is changing. The majority is done in infectious-disease testing, but as we go forward, we expect it to grow in other areas, such as genetic testing, prenatal, oncology, and pharmacogenomics,” Hill says.

Hill expects these tests to eventually surpass the infectious-disease market, but after they overcome the challenges presented by complexity. “These are not simple organisms where you can identify one or two sequences and confirm presence of the organism. New technologies will be needed for genetic and oncology testing,” Hill says.

Methodology Matters
“There are about 30 different types of biological tests—some protein, some gene, some sequencing. Each is different. The challenge is comparing them and determining which is more reliable, specific, or sensitive,” says Atul Butte, MD, PhD, assistant professor of medicine (medical informatics) and pediatrics at Stanford University in Stanford, Calif.

But there are some soft standards. “The biggest molecular diagnostics is nucleic acid testing,” Sullivan says. New processes have already improved this method.

“Earlier nucleic acid amplification tests had problems with inhibition. Inhibitory factors in the samples were not eliminated during sample processing, resulting in inhibition of the amplification reaction and false negative results. New sample-processing procedures, such as target capture, purify the samples and correct this problem,” Hill says. Transcription-mediated amplification (TMA), real-time PCR, and microarrays have contributed to wider availability and better results.

New spectroscopic methods are improving detection. Centice’s MMS Raman Spectrometer uses a coded wide-area aperture, instead of the conventional slit entrance, leading to more signal without a proportional increase in noise. The technology can be used to boost the sensitivity of other spectroscopic instruments, such as fluorescent and Raman systems.

“You can divide labs by those that use FDA-cleared tests versus non-FDA-cleared tests. Hardcore molecular labs will use laboratory-developed assays, or home brews, and real-time PCR,” Hill says, noting that real-time PCR is used widely but that not many of these tests have been cleared by the US Food and Drug Administration (FDA).

Proulx believes that the use of real-time PCR is an obvious trend. “Real-time PCR was not so routine a few years back. Now if one were to open a molecular diagnostics lab, it would be the first technology considered,” he says. “You could say the same thing of FISH [fluorescence in situ hybridization].”

Proulx says that the technical advances have allowed the expansion of molecular-diagnostics methods, allowing a wider variety of potential disease markets and clinical utilities. “HIV genotyping has the obvious benefit of helping to determine treatment. But the value of HCV genotyping was not immediately relevant. We need to know what the information will allow us to do,” Proulx says.

Butte thinks one of the recent advances to have a huge impact is the clearance by the FDA of the first microarray. Roche Molecular Systems Inc’s AmpliChip Cytochrome P450 Genotyping Test was cleared for use with the Affymetrix GeneChip Microarray Instrumentation System, manufactured by Affymetrix Inc of Santa Clara, Calif, in late 2004.

“There have been a number of papers over the past 10 years that show these chips can help to distinguish diseases. For instance, a recent paper differentiated two subtypes of lymphoma with a big difference in survival and, therefore, implications for treatment. Doctors thought this was one disease, but by looking at all the genes, they discovered it was two,” Butte says.

Let the Machine Do It
Microarrays are often made using robotics, and now automation can help run them as well. Nanogen began shipping its NanoChip 400 last year. The system combines sample- and reagent-handling robotics with detection to allow labs to perform multiple molecular applications. The user configures the blank microarray template with a defined panel of genetic markers at the time of testing. “The instrument automatically creates the array, puts the sample in, processes it, and reports the result,” says Nanogen’s Proulx, who feels that the opportunity to automate processes will be used more.

“With an automated nucleic acid extraction instrument, the sample-preparation side can be automated as well. Some companies are now offering start-to-finish real-time PCR. These are often designed to deal with smaller sample numbers, but with more of them, there is the potential for greater adoption in large and small labs,” Proulx says.

“You probably do need a certain volume to justify initial setup costs of automation, but it can help even in smaller labs,” says AMP’s Lyon, noting there are different levels of automation. “A sample extractor can range from eight specimens to 96,” she says.

Hill notes that Gen-Probe offers three different systems with varying levels of automation. The company’s three Direct Tube Sampling (DTS) System products can process 400, 800, and 1,600 results in 8 hours.

There are also varying degrees of automation. The company’s TIGRIS DTS automates the entire process, eliminating all manual preparation. It was approved by the FDA in late 2004 for use with Gen-Probe’s APTIMA COMBO 2 assay, an FDA-approved amplified nucleic acid test (NAT) for simultaneously detecting Chlamydia trachomatis and Neisseria gonorrhoeae. The company is working to expand the test menu.

“The system is generally used by labs that process at least 150 samples per day, with some of them processing over 1,000 per day,” Hill says.

Volume is just one of the factors that impact a decision to automate. Proulx suggests equipment costs, staff, turnaround, and other issues can influence whether technology will enhance workflow and revenue. “Most labs start to look at automation when their volume suggests they can no longer accomplish a typical 1-day turnaround. But they should also ask whether they run the test every day or wait for batches. Is one person spending the entire day running batches? Automation is a trade-off, but it may be worth it,” Proulx says.

Stirring the Pot
Automation may be able to help with some of the steps involved in laboratory-developed assays, but even so, these tests take more time and labor. “Laboratory-developed assays do take additional staff to design and do take more time. Another challenge lies in the difficulty of standardizing such a test between labs,” AMP’s Lyon says.

However, Lyon continues, they fill a gap left by commercial entities that won’t produce specific tests because there is not enough volume to justify the cost of development and manufacturing. “Some diseases are very rare and are well served by a laboratory-developed assay,” Lyon says.

Who Knew It When?
Though it may seem as though the laboratory-developed assays would present the greatest challenge for physicians interpreting the results, the problem is one the field faces at large. Labs are assuming the responsibility. “I don’t think it’s the problem of the ordering physician. It’s an interaction between the clinical lab and the physician. What method does the lab have, and what will give the result the physician seeks?” Proulx asks.

“The health care provider may not have the molecular expertise to interpret the results, so he or she should call the lab if the results are not understood. The lab personnel also can help in suggesting follow-up care for the patient and, in the case of inherited disease, for the family members,” Lyon says.

Physicians can also benefit from communication on the ordering end. “Some tests are very appropriately ordered, but other times, the physician may have really wanted a protein assay when a molecular assay was ordered instead,” Lyon says.

Labs can counteract this with education through lectures and ground rounds. “Many labs offer test summaries with indications for ordering and interpretation,” Lyon says.

Show Me the Money
As the tests become more routine, physician use becomes more appropriate. Similarly, reimbursement becomes more reasonable or easier to obtain. “Some tests are well accepted and reimbursed adequately. Others are not reimbursed at the level they should be, and there may be a few that are not reimbursed at all. But overall, insurance has been reasonable in understanding the significance of genetics and molecular diagnostics,” Lyon says.

“There are CPT codes available for most of the molecular methods, including nucleic acid extraction, nucleic acid amplification, and real-time PCR. Effective January 1, there is also a CPT for microarrays. So labs now have codes for reimbursement,” Proulx says.

Noting that not all payors reimburse at the same rate, Proulx suggests that labs do their homework before implementing the tests. “What is the reimbursement? What will the payor pay? Will it be cost-efficient? It may not be purely profitable, but it may improve the standard of care enough to impact overall performance,” Proulx says.

Coming To a Lab Near You?
Whatever the reason, many clinical labs are deciding that bringing molecular in-house is the right thing to do. The global market for molecular diagnostics in 2005 was worth $6.5 billion, approximately 3.3% of the total diagnostics market and approximately 14% of the in vitro diagnostic market.1 By 2010, the molecular diagnostics market is projected to expand to $12 billion; and by 2015, it will be worth $35 billion.

Sullivan, drawing on data from a CHA Advances Report, says, “The clinical market for molecular diagnostic products has increased from less than $50 million to more than $1 billion, and sales are expected to exceed $3 billion by 2008.”

It’s clear that the value, tools, and need are there, but is the foundation, expertise, and capital available? Everyone’s interested in molecular diagnostics, but the tests need to be clinically useful and integrated smartly. “Molecular diagnostics is important to the clinical lab, and more hospitals want to bring tests in,’’ Stanford’s Butte says, adding that they are not central to every lab — yet.

Renee DiIulio is a contributing writer for Clinical Lab Products.

Reference
1. Molecular diagnostics: Technologies, markets, and companies. Jain PharmaBiotech. Jan 2006. Available at: http://www.researchandmarkets.com/reportinfo.asp?report_id=39070. Accessed February 15, 2006.