Diagnostic tests have traditionally been about identifying a patient’s disease. Today, however, laboratories are being asked to go one step further and help determine what follows the diagnosis, ie, which treatment should be implemented.

“It’s become a two-stage process,” says Stephen Little, PhD, CEO, DxS, Manchester, England. “First, what disease does the patient have? Conventional diagnostics will continue to play a role answering this question. Once the disease is determined, the next question is what to do about it? Assays, which fall into the category of personalized medicine tests, can help to determine which treatment or drug is best for that particular patient.”

The promise of personalized medicine is, therefore, better patient outcomes through earlier diagnoses and smarter treatments. According to Edward Abrahams, PhD, executive director of the Personalized Medicine Coalition (PMC), Washington, DC, the PMC defines personalized medicine as optimizing medical treatment through the use of molecular analysis to improve quality of life and health, and potentially reduce the overall health cost.

“We don’t restrict the definition to genetics or genomics,” Abrahams says. “It’s anything that will facilitate better medical decisions—in other words, will link diagnostics and therapy—and point to better medical outcomes across the board.”

Medicine has always been personal—patients are individuals, after all—but the advent of personalized medicine is tied to the development of tools that allow the personalization of diagnostics and therapy. Diseases are being broken down to levels of understanding that permit personal and actionable testing. “For instance, having breast cancer in the future might mean more than just a pathology report

based on a microscopic exam of the tumor. Rather, a patient will be tested at the molecular level to

better understand the prognosis as well as which targeted therapy will have the best outcome for the patient,” says David Okrongly, senior vice president of molecular diagnostics for Siemens Medical Solutions Diagnostics, Tarrytown, NY.

Less than 1/10th of 1%

Improving the outcome so that it is the “best” means increasing efficacy and/or decreasing risk. Personalized medicine can achieve this by helping to identify the best treatment, the most efficacious drug, the maximized dose, and/or the optimal duration. “As drugs become more toxic and efficacy decreases in the general population, using biomarkers to target individuals with a good response increases effectiveness,” Little says.

Siemens’ TruGene DNA sequencing system helps locate clinically relevant mutations in HIV patients; research kits are available for HCV and HBV genotyping.

Drugs such as codeine, which do not work for everyone but have few side effects, are more easily prescribed on a trial-and-error basis, Little suggests. In contrast, more dangerous medications, such as those used in oncology, carry greater risk along with a high economic cost and are ideally suited to personalized medicine testing. “There is more value to this testing from the clinical perspective,” Little says.

Of course, this value must be proven before these tests are accepted into mainstream care. Some tests, like those for HER2 in breast cancer tumors or CYP2C9 and VKORC1 for warfarin dosing, have become standards of care. Many others are still in early adoption stages or development. Tim Uphoff, PhD, the clinical consultant directing the molecular pathology lab at Marshfield Laboratories, Marshfield, Wis, expects personalized medicine to grow exponentially in the future but estimates that it currently makes up less than one tenth of 1% of all laboratory testing. “The impact of personalized medicine testing is limited right now simply because we do not know enough about variations in the genome to allow us to predict the outcome in most cases,” Uphoff says.

The biggest areas for these tests are microbiology, virology, and oncology. “The focus in personalized medicine is on genetics, but it is also used in the microbial realm, such as HIV and HCV [hepatitis C virus],” Uphoff says. Genotyping of HCV can help physicians determine the appropriate treatment course. “A physician may choose to treat a more resistant genotype [of HCV] with a higher dose for a longer period of time before reevaluating the patient’s condition,” Uphoff says.

High Value, High Cost

Unfortunately, the high value of these tests also translates into high costs. Okrongly suggests they can cost as much as $1,000. In addition, the protocols tend to be low volume, high complexity, labor intensive, and specialized.

“These are not high-revenue tests, and they currently offer little financial gain for the laboratory at this time. Often, these tests are not reimbursed at a level that covers the cost associated with testing,” Uphoff says.

Yet, when factored into the overall cost of a patient’s care, they do become cost-effective. “Typically, this type of oncology diagnostic costs more, but it helps to ensure that the $5,000 spent on the cancer therapy is not wasted. So, overall, the tests save money,” Little says.

The higher costs are associated not only with the demands of the test on the lab, but also the demands during development.

“The R&D required for the validation and approval of these tests is coming at a much higher price than for traditional diagnostics,” Okrongly says. Uncertainty regarding regulatory requirements [the FDA has released and received comments on a second draft of its IVDMIA guidelines] has also impacted manufacturers’ ability and/or desire to move forward with new tests.

Okrongly suggests that an economic shift is under way in medicine, where more patient resource dollars are directed toward the beginning of the disease process, when interventions have a greater chance of impacting a positive outcome, rather than toward the more advanced end of the continuum (“where care is expensive and usually futile,” Okrongly says).

Consequently, many argue that billing and reimbursement should increase for these types of tests.

PMC’s Abrahams notes that part of the organization’s mission is to make the case for greater investment in the area of personalized medicine. Some of that investment will go toward automating the tests. Automation will be key to increasing their cost-effectiveness, particularly for the clinical laboratory.

“Our plan is to automate and simplify these tests so lab personnel can handle the volume and are freed up from the routine manual operations to take on more valued tasks,” Siemens’ Okrongly says.

These tasks may include interpretation of the results. “One of the biggest impacts on the clinical lab that will result from personalized medicine will be a change in the way these results are reported. They require more interpretation because they refer to a drug and the patient and a response,” says Vincent Fert, president and CEO of Ipsogen, whose US headquarters are in New Haven, Conn.

Value Before Volume

Although none of these tests are expected to produce a significant volume of testing individually, together they will have a large impact. Many of the new tests will supplement conventional diagnostics rather than replace existing tests.

Currently, tests developed for personalized medicine are highly complex and labor intensive. Photo courtesy of Exagen Diagnostics Inc.

“I think occasionally they’ll replace an existing test, but oftentimes, it will be an expansion of the testing that would be performed routinely for a particular disease. For example, HER2/neu testing wasn’t done in the past but is now an additional test performed on breast cancer patients,” says Tom Williams, MD, chief scientific officer for Exagen Diagnostics Inc, Albuquerque, NM, and professor of pathology at the University of New Mexico School of Medicine, Albuquerque.

Fert concurs, adding they may also provide validation for existing tests. Fert expects that over the next 5 years smaller labs will begin performing these tests. Currently, he notes, they are most often performed in laboratories approved for high-complexity testing.

The addition of personalized medicine to testing menus will probably occur organically, with individual laboratories adding tests as the volume of requests increases.

“Many labs tend to run on volume and price: If they can get a sufficient volume at a reasonable price, they’ll add an assay rather than continue to send it out,” Little says.

Volume, however, cannot be expected to increase for newer tests without the data to support their clinical use. “There are tests on the market not being utilized because it is not exactly clear to physicians how valid the information is or how clinically useful it is,” Abrahams says.

Regulatory clearance can have a large impact on adoption, in part because approval requires significant and clinically valid data. Legal requirements push adoption even further. Use of one of the most common drugs in this class, herceptin, requires a related diagnostic determining the patient’s eligibility (the overexpression of HER2) prior to use of the drug. In contrast, the label for mercaptopurine (brand name Purinethol) notes that genotypic and phenotypic testing for thiopurine S-methyltransferase (TPMT) are available, but no recommendation is made. Subsequent adoption of the TPMT test has been slow, Little says.

Marshfield Laboratories’ Uphoff concurs, noting that testing for cystic fibrosis did not take off until specific professional guidelines recommended the test. Evidence-based guidelines help to summarize clinical validity, change reimbursement policies, and provide physicians with more confidence in their treatment plans. They are useless, however, if physicians are uncomfortable ordering the tests and stick to conventional methods.

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Selling Personalized Medicine

“The need to educate physicians about how to use these tests will be crucial to their success,” Williams says. Some call it old-fashioned selling. “Doctors need to be persuaded that the information they get from an assay is better than the information they would receive without it,” Little says.

Introducing a drug and diagnostic together can help to push adoption, in part because it shows a clear link to therapy. “The new diagnostic stands to gain from the marketing push for the new drug which educates the market and encourages acceptance,” Ipsogen’s Fert says.

As companies develop more products, awareness in the medical community is expected to increase. It’s currently a niche market, points out Jim McClintic, Exagen’s CEO. “When diagnostic companies develop these tests for larger markets, more awareness and more adoption will follow.”

The company is banking on it—it’s currently developing tests to differentiate inflammatory bowel syndrome, the market for which McClintic estimates is 3 million patients per year. He compares this to breast cancer recurrence testing, which impacts about 150,000 to 175,000 patients.

Siemens also sees a rosy future for personalized medicine. Okrongly shares company market projections that point to a fivefold increase within the next 10 to 15 years.

The marketplace will likely be crowded. “Because genomics are so diversified and there are so many genes involved in every disease state, there will be several diagnostic tests competing for the same market, and the first test might not always be the best,” McClintic says. But he also expects that same diversity to support multiple tests in the market, since they may provide answers to slightly different questions.

Of course, eventually the questions will expand, from how to treat this disease to how to prevent it. “Down the road, we would like to be able to identify an individual’s risk for certain outcomes, such as heart disease or obesity, but we don’t know enough yet. We’ve started with the low-hanging fruit,” Uphoff says.

Williams points out that there will be plenty of opportunities and points to the many medical niches, disorders, drugs, and genetic variations available to work with. “Most will play out in complex or multifactorial diseases, such as cancer or heart disease, but they will impact diagnostic and prognostic tests,” Williams says. Ideally, they will enable physicians to answer the question, “What’s next, doc?”

Renee DiIulio is a contributing writer for CLP. For more information, contact .


Unless you’ve been living in a test tube, you have probably heard some rumblings about the personalized medicine revolution. And you’ve probably also heard of some of the paradigm shifting foot soldiers: herceptin and HER2, warfarin and the CYP2C9 and VKORC1 genes, Gleevec, and tyrosine kinase. They are the first examples mentioned in any discussion of personalized medicine, but others exist, too.

Some are already commercially available; others are still in development, but their adoption will depend on their clinical usefulness and the data that supports them. However, it may not be entirely up to the medical community. Patients have a say, too (they provided some push for drugs such as herceptin, Gleevec, and Iressa), though some question whether they should.

Edward Abrahams, PhD, executive director of the Personalized Medicine Coalition, Washington, DC, thinks patients will play a role, however. “I believe patients are going to be more aggressive in demanding that their therapies involve less trial and error but are more targeted,” Abrahams says.

With the Internet providing a seemingly endless supply of data, it’s easy for patients to find information relevant to their particular condition. It’s also easy to find information that is not so relevant as well as just plain wrong. It is the physician’s job to set the patient straight. Patients and physicians will have to work together to decide on appropriate treatments.

Abrahams expects that at some point we will reach a “tipping point,” where we will no longer talk about personalized medicine. “It will just be the practice,” he says.

— RD