For many, the Human Genome Project was a smashing success. Finishing early and with greater accuracy than expected, the International Human Genome Sequencing Consortium, led in the United States by the National Human Genome Research Institute (NHGR) and the US Department of Energy, published a scientific description of the finished human genome sequence in late 2004.

The work estimated the number of human protein-coding genes to be in the range of 20,000 to 25,000, fewer than the 30,000 to 35,000 originally expected.1 The data included an assessment of the quality of the finished human-genome sequence, which found that, “The finished sequence covered more than 99 percent of the euchromatic (or gene-containing) portion of the human genome and was sequenced to an accuracy of 99.999 percent, which translates to an error rate of only 1 base per 100,000 base pairs—10 times more accurate than the original goal.”1

This information promised big breakthroughs that fueled interest in the field, but its value was more often seen in research than clinical health care. As it first became clinically useful, genetic information did a great job of diagnosing disease and determining predispositions, but it rarely seemed to offer information on how to treat the disease and positively impact outcome.

And then that changed, too. As it turns out, gene sequences that offer information about the presence of disease can also provide clues as to how the individual’s condition will respond to various treatments—particularly the disposition, safety, tolerance, and efficacy of drugs. Early indications suggest this means a better outcome for patients, along with benefits to health care that include rational drug design.

Enter pharmacogenomics, a term developed from pharmacology and genomics to describe the science of personalizing drug therapy to individual genetic codes. Related diagnostic tests have not flooded the market yet, but the US Food and Drug Administration (FDA) may force that to change by encouraging the use of pharmacogenomics in drug development. The organization believes pharmacogenomics, which it shortens to PG, is one of the new fields that holds the potential to speed the clinical utility of innovative research developments, benefiting patient care and health care economics.

No one is yet inclined to disagree, at least not until more data has been compiled. In the meantime, some treatments are already available—indeed, even standard—and the number is poised to increase. The associated diagnostics fall under the purview of the clinical labs, which have already absorbed them, usually with molecular biology. But labs are only just starting to prepare for the day when pharmacogenomics become part of the standard of care.

The Standard of Care?
“That day is still 4 or 5 years away, but it is a disappointing length of time,” says Michael Murphy, president and CEO of Gentris Corp. He notes that the two or three tests that have already become a standard of care took 20 years to get where they are today.


According to the National Center for Biotechnology Information (NCBI), pharmacogenomics and pharmacogenetics can be used interchangeably.1 For logophiles, their actual definitions, according to the NCBI follow:

Pharmacogenomics is the general study of all of the different genes that determine drug behavior.1

Pharmacogenetics refers to the study of inherited differences in drug metabolism and response.1


1. National Center for Biotechnology Information. A Science Primer. Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources; One Size Does not Fit All: The Promise of Pharmacogenomics. Available at: [removed][/removed] Accessed April 21, 2006. – RD

A PricewaterhouseCoopers report on personalized medicine and pharmacogenomics published last year found that industry consensus expects pharmacogenomics to become “part of the mainstream” in 5 to 10 years..2 Ten years also represents the amount of time the report expects pharmacogenomic data submittals to become mandatory for FDA approval.2 “Yet, the sooner they are put into practice, the sooner we can begin to reduce one of the leading causes of death,” Murphy says.

Reports, such as the now-famous 1999 Institute of Medicine report on medical error, have put the estimated number of deaths related to medical error anywhere from 44,000 to 98,000 annually. A report published in 2000 in the Journal of the American Medical Association by Barbara Starfield, MD, MPH, estimated an even higher number of annual deaths from medical error at 225,000. Of these, she attributes 106,000 deaths to nonerror, adverse effects of medications.

Pharmacogenomics experts, including Murphy, believe that this number can be reduced significantly, if not altogether, by using genetic codes to determine whether an adverse drug reaction is possible, as well as to avoid wasting time on drugs or doses that either will not work or will cause severe side effects.

Why So Long?
Because the field is relatively new, few tests are in practice. It takes time to develop new diagnostics as well as to develop guidelines, educate physicians, and secure reimbursement.

“I think most traditional labs look for demand, so physicians need to first ask for these tests. The demand may need to be directed by the companies producing the tests. We want to educate the doctors on where this will help, how to use the test, and which patient population might benefit,” says Judith C. Wilber, PhD, vice president of technical operations for XDx.

We also need well-established standards and guidelines, according to Milhan Telatar, PhD, scientific director for molecular genetics at Specialty Labs. “We must consider the methodologies for selecting testing profiles and interpretation of results to ensure clinical efficacy. When we set guidelines—which we haven’t yet—everyone will start ordering these tests,” she says.

Which Technology Will Dominate?
Development of guidelines may be a challenge since pharmacogenomics relies on a variety of technologies, some new and some currently in use. However, the majority of these methods requires extended time and advanced expertise, including techniques such as nucleic acid extraction and amplification, real-time PCR, microarrays, and flow cytology.

“I don’t think any technology in particular will dominate. There will be a number of different technologies, some existing and some new. I think it’s dangerous to predict domination by one technology. We need to be open to using a wide range. It’s not the technology that makes the difference; it’s what you learn from the test. The technology is merely a means to an end,” says Mara Aspinall, MBA, president of Genzyme Genetics, and a board member of the Personalized Medicine Coalition.

But the technology does matter to labs that are restricted by budget or expertise. “The platforms coming out for pharmacogenomic tests are unique and tend to be tied strictly to that test, which is not very helpful. It’s unlikely a lab can take on the expense of buying a new platform to offer just a handful of tests,” says Gentris’ Murphy. He feels standardization within testing will make it easier for kit developers, who can then develop tests on a common platform.

“The closest thing to that right now is real-time PCR. A number of companies base products on that platform,” says Murphy, who notes that sequencing is a second popular option. But he expects that in the long term, microarrays may dominate.

“Once some of the clinical and regulatory hurdles are overcome, the technology that makes the most sense is microarray. Any time we can do things with multi-plexing, either amplification or even detection, it can significantly reduce cost and complexity. But for that to happen, we also need a platform that can be completely automated,” Murphy says.

Following Herceptin’s Example

Herceptin could be considered the poster child for pharmacogenomics. Developed by Genentech (South San Francisco, Calif), Herceptin was originally not found to be effective in overall clinical trials. But when the results were evaluated with genetic makeup in mind, women with human epidermal growth factor receptor 2 (HER2)-positive metastastic breast cancer were found to have improved response rates to the treatment than women who tested HER2-negative.

While the drug underwent the approval process at the FDA for this use, Genentech worked with Dako (Glostrup, Denmark/Carpinteria, Calif) to develop a diagnostic test that would accurately determine whether a patient had HER2-positive or HER2-negative breast cancer. Both the drug and the diagnostic were approved in 1998. In 2002, Genentech received approval to add information about FISH diagnostic tests to the labeling as well.

The story realizes the promise of pharmacogenomics. By focusing on a smaller segment rather than the general population, the drug was saved — drugs found to not have efficacy during clinical trials are abandoned, along with the time and money put into their development. However, with the targeted analysis, Genentech had a viable drug that, though not a “blockbuster,” now plays a specific role in HER2-positive breast cancer patients.

These patients also benefit, obtaining a treatment that increases their survival rates and outcomes and which may have otherwise remained forever unavailable had it needed to show clinical efficacy within a significant portion of the general population.

The decision to develop a diagnostic that would be approved at the same time as the drug itself assured that when Herceptin was cleared by the FDA, it was immediately available for effective use. Dako also benefited with a new product linked to a successful drug. Testing for the HER2 gene has become a standard of treatment in breast cancer.

“Herceptin and HER2 NEU testing are pretty much required if you are going to use the drug because only 25 percent of people can respond to it,” says Wilber. Hence, Herceptin illustrates the pharmacogenomic promise well, showing benefits from rational drug design, more efficient use, and better patient outcomes. -RD

XDx’s Wilber agrees, saying that molecular biology diagnostic techniques, particularly messenger RNA (mRNA) expression, are time and labor intensive, so robotic technologies would be welcome. “So far, multi-plexing technologies haven’t been as adaptable as they may claim, but it looks as if development is coming along and we may be able to simplify some of these procedures in the not-too-distant future,” she says.

What About Regulations?
Simpler technologies may mean less complicated quality-control and quality-assurance methods. “Those tests that involve multiple markers, and a lot of them do, require a lot of quality control,” Wilber says.

XDx developed AlloMap molecular-expression testing for heart transplant-patient management as a noninvasive method to routinely monitor these patients for the risk of rejection. According to Wilber, the test quantitates mRNA on 20 different genes.

“All of those real-time PCR reactions have to work together in order to get the correct answer on every single gene, so a lot of quality control has to be developed specifically for those genes. If using a test developed in your own lab, then you are responsible for all of the validation, which creates a larger burden than a kit test,” Wilber says.

However, this is no different than with any other test, laboratory developed or otherwise. “The quality program should ensure reproducible and highly efficacious results in a timely manner,” Telatar says. She points out that standards and guidelines address these issues.

Similarly, guidelines also address privacy and data issues, but many feel that no new standards will be necessary to cover the data produced by pharmacogenomics. Standards, such as those established by the Health Insurance Portability and Accountability Act, are expected to handle current needs.

“The data itself is not too different from the data that everyone is used to getting, though there are always other concerns we don’t see in traditional clinical lab medicine, such as the implications for siblings and parents,” Murphy says.

“I caution everybody to think about whether these tests are really any different,” says Genzyme’s Aspinall, who acknowledges that implications may exist for family members. There are times when the code is inherited because it is part of your genes, but it lies only within your genes and not necessarily the family code, she says.

“The patient may handle the results differently so that they may choose to share them less causally than their cholesterol level, but for the lab, the level of privacy and confidentiality is the same no matter what the test is,” says Aspinall.

How Many Tests Should We Expect?
“The number of pharmacogenomic tests coming to labs will definitely be increasing,” Murphy predicts. He suggests FDA activity, particularly any regulations that affect labeling, will spur growth. “I don’t think physicians will ignore that type of change, particularly one that says highly recommended, when the potential outcome is serious adverse drug reactions in patients.”

Aspinall believes the tests will increase simply because the technologies “allow us to monitor disease and reaction to disease far more effectively. They will be more needed as therapy and treatments become more personalized and targeted,” she says.

Despite any obstacles, some of the tests are already beginning to become standard in many areas. Human epidermal growth factor receptor (HER2) testing is routinely used to determine HER2-positive metastastic breast cancer patients, who are then eligible for treatment with Genentech’s Herceptin, which has been shown to improve outcomes in these specific patients.

Such recommendations are often included on the label. The information for Strattera (atomoxetine HCl), an Eli Lilly and Co drug for attention deficit disorder, notes that there are laboratory tests to determine people with reduced activity in the cytochrome P450 2D6 (CYP2D6) enzymatic pathway, which metabolizes atomoxetine. Slow metabolizers are less likely to benefit from treatment and may require additional medication or different doses.

Screening patients before they take medications will impact the number of these tests for labs, but because the populations are clearly defined, they will likely not reach the volume that would be required for a blockbuster drug. Clinical monitoring, however, offers opportunity through repetitive testing, such as that done by XDx.

Even though the population is very defined — heart-transplant patients — the test is not a one-time test. The test does not determine genetic makeup but rather looks at the status of the immune system over time, so it is performed more than just once, Wilbur says.

Murphy expects the biggest increase in pharmacogenomic testing to come from drugs currently in development, and that development will stay in the domain of diagnostic companies for the near future. Whether they will work in conjunction with development of the drug, as with Herceptin and the HER2-diagnostic (see sidebar), or after the drug has been approved by the FDA, will likely depend on the individual situation, though more collaborations are expected.

“The idea of the FDA is that the time it takes to get a diagnostic test out is shorter than that for a drug, so it may be possible to come up with a good marker and have it ready for when the drug is approved,” XDx’s Wilber says.

“The approach is valuable if the drug itself warrants it,” says Genzyme’s Aspinall, offering Herceptin as an example. The decision then impacts the lab, because physicians have a test that can maximize use of the drug. “Physicians can use it, and it has an impact on patients. When there is reason to perform the test that will change the course of care, there exists more demand,” says Aspinall. “It’s an exciting future where we can continue to add value to patient care by adding more and more accurate, important, and relevant testing.”

1. Human Genome Project Information. “International Human Genome Sequencing Consortium Describes Finished Human Genome Sequence Researchers Trim Count of Human Genes to 20,000-25,00.” October 20, 2004. Available at: Accessed April 21, 2006.

2. Global Technology Centre, Health Research Institute. “Personalized Medicine: The Emerging Pharmacogenomics Revolution.” PricewaterhouseCoopers. February 2005.

Renee DiIulio is a contributing writer for Clinical Lab Products.