14 HASTINGS CENTER REPORT September-October 2010

A woman with breast cancer takes a genetic test that predicts how active the tumors are and whether the

benefits of chemotherapy outweigh the risks of side effects.•

A newlywed couple sends saliva samples to a start-up company to test for carrier genes for over one hundred

inherited diseases, many of which are incurable or lethal.•

A heart transplant patient takes a blood test that de-tects patterns in gene expression to check for signs of rejection, making an invasive biopsy unnecessary.

Each of the tests described above either exists or is under development. Now, ten years after the re-lease of a working draft of the human genome,

major changes have made their way into medical prac-tice, the marketplace, research, and policy. Prices of full genome scans are falling, enabling faster and cheaper ge-nome sequencing to drive developments in clinical and consumer genetic testing. Ten years ago, mapping the entire genome cost about three billion dollars. In August 2009, the eighth person to have his entire genome mapped and published did it at a cost of fifty thousand dollars. Today, biotechnology companies say that they

are doing it at a fraction of that price, for a few thousand dollars.

Over two millennia ago, Hippocrates emphasized the importance of individualizing medical care, proclaiming, “It is more important to know what sort of person has a disease than to know what sort of disease a person has.” Personalized medicine attempts to do this by tailoring treatment to individual patients. The model is based on the use of information such as a patient’s values, fam-ily history, or data from laboratory tests. Most recently, the concept has expanded to include testing for genomic information, which encompasses genes and their protein products. Establishing a molecular profile has the poten-tial to improve the effectiveness of treatments and reduce adverse side effects, as well as save money by avoiding unnecessary care.

The federal government has demonstrated its com-mitment to personalized medicine. In 2004, the Food and Drug Administration took one major, early step by launching the Critical Path Initiative to help incorporate genetic advances into the development of medical prod-ucts and drugs. President Obama’s support for personal-ized medicine was evident in 2006 when, as senator, he introduced a bill that would accelerate genomic research, diagnostics, and treatments. Although the bill was never acted upon, a similar bill was introduced last May in the House of Representatives. Additional support from the FDA included the creation of a new position last year to coordinate genomics activities within the agency. In March, the National Institutes of Health announced that it would establish a voluntary genetic testing reg-istry by 2011 to provide comprehensive information about the more than sixteen hundred clinical laboratory genetic tests currently available.

Behind the justifiably high expectations raised by per-sonalized medicine are a number of ethical issues, which are explored in the essays that follow. Does genetic test-ing lead to overall better patient outcomes? The hope is that research will reveal guidelines on who can and can-not benefit from particular treatments. But rather than revealing bright lines between efficacy and inefficacy, research often yields “ragged edges”—some patients who benefit a lot from an intervention, and many patients

Shara Yurkiewicz, “The Prospects for Personalized Medicine,” Hastings Center Report 40, no. 5 (2010): 14-16.

EssaysPersonalized medicine—the customization of medical treatment to an individu-al’s genetic profile—aims to both improve outcomes and control costs. But recent

news, including scandals involving direct-to-consumer genetic tests and ques-tions about targeted cancer therapies, has exposed many ethical hurdles. They are explored here by ethicists, a patient, a medical student, and a consumer advocate.

The Prospects for Personalized Medicine

BY SHARA YURKIEWICZ

September-October 2010 HASTINGS CENTER REPORT 15

who benefit a little. What evidence qualifies as a benefit? Who decides who gets a treatment? Who pays for it? Other questions concern the role of direct-to-consumer genetic test-ing companies, which have recently been criticized for inac-curacies and deceptive practices. There is also the challenge of agreeing upon ethical policies for procuring the massive amounts of human tissue for the genetic research that is need-ed to move personalized medicine forward.

Custom Drug Treatment

One of the most promising areas for genetic testing lies in pharmacogenomics, or

how a patient’s genetics influ-ences his or her drug response. Drug therapy is rarely clear-cut: if one hundred patients with a particular condition are given the standard dose of a medication, on average sev-enty or eighty of them will benefit, some will not, and a few may suffer severe adverse effects. Proponents of pharma-cogenomics eventually hope to popularize the “Dx-Rx paradigm”—a genetic test (Dx) followed by a prescription (Rx). “A treatment is no longer just a molecule,” says Lydia Pan, director of science policy at Pfizer, which, like many other pharmaceutical companies, is developing drugs that are tar-geted to specific genetic variants. “It’s a molecule plus a body of knowledge telling us how to use it.”

About 10 percent of labels for drugs approved by the FDA now carry information on genes and drug response. One of these drugs is abacavir (Ziagen) for HIV. Nearly all patients can take the medication relatively safely, but approximately 6 percent of patients are hypersensitive to it, developing a severe allergic reaction that can be lethal. In 2004, research-ers discovered that virtually the entire toxic reaction corre-lated with a single genetic variant. In July 2008, the FDA added a recommendation to Ziagen’s label that individuals should be screened for this particular variant before the drug is prescribed.

Within cancer care, genotyping tumors can increase the odds that a drug will be safe and effective by predicting which medications will work against which tumors—or whether certain medications will work at all. One of the first genetic tests developed to use before treatment, approved in 1998, is for HER2, a protein that indicates aggressive cancer when found in high amounts in breast cancer cells. Herceptin is a drug that attacks only HER2-positive tumors. It is useless and potentially dangerous for women whose tumors do not

express the protein. More recently, genetic testing of tumors has been used to identify patients with lung cancer, colorec-tal cancer, leukemia, and lymphoma who might benefit from certain medications, including new drugs targeted to particu-lar genetic traits. At Massachusetts General Hospital, oncolo-gists have recently begun analyzing nearly all new patients’ tumors, looking for 110 abnormalities carried on thirteen genes.

For now, however, the use of genetic screening to make decisions about drug treatments can be confusing to doctors and unconvincing to third-party payers. A prime example is coumadin (Warfarin), a blood thinner used to help prevent

blood clot formation. Over thirty million prescriptions are written annually, but dosing is notoriously dif-ficult since patients vary widely in their response to the drug. Approximately 40 percent of the variabil-ity in dose response is due to common variations in two genes—one involved in drug metabolism, and the other in the activation of blood-clotting factors. In January, the FDA updated coumadin’s label to include pharmacogenomic-guided dosing ranges, suggesting that physicians consider pa-tients’ genetic factors when dosing the drug. But the label does not explicitly rec-

ommend testing for all patients who may receive coumadin. Medicare does not cover these tests, which cost fifty to five hundred dollars, citing a lack of evidence for better patient outcomes compared to existing dosing protocol.

Many Tests, Little Quality Control

There are dozens of genetic tests available in the United States that consumers can purchase on their own. Because

the direct-to-consumer market is rapidly expanding, the exact number of providers is difficult to quantify. Estimates range from thirty to more than seventy providers, with some offer-ing tests that focus on health information and disease risk and a few providing complete genome sequencing. Major DTC genetic testing companies include 23andMe and Navigenics, which are in Silicon Valley, and deCODE, in Iceland, and test prices range from four hundred to a thousand dollars. (For entire genome sequencing, Knome, in Boston, charges just under seventy thousand dollars, and Illumina, in San Diego, charges just under twenty thousand.)

Both the results and the interpretation of DTC tests can be misleading or inconsistent among companies. Although

Establishing a molecular profile has the potential

to improve the effectiveness of treatments and reduce

adverse side effects, as well as save money by avoiding

unnecessary care.

16 HASTINGS CENTER REPORT September-October 2010

DTC companies use clinically validated genetic mark-ers for predicting disease risk, they are not necessarily the same markers or number of markers. In an article in Nature in October 2009, scientists said they submitted five DNA samples to both 23andMe and Navigenics to test for risk of thirteen diseases. For seven of them, including Crohn’s dis-ease and type 2 diabetes, at least one sample received con-tradictory predictions from the two companies. Most of the current data about risk prediction come from genome-wide association studies using populations primarily of European ancestry, which makes extrapolating results to other ethnic groups difficult. Although many companies acknowledge that a trained professional could be useful for interpreting information, only a few companies have genetic counselors on staff.

The FDA has just begun to show an interest in regulat-ing DTC tests, triggered in May when Pathway Genetics announced plans to sell genetic tests in drugstores. Last summer, the FDA sent letters to several genetic testing com-panies, informing them that they need approval to market medical devices. In late July, Congressional hearings on DTC testing included a new Government Accounting Office “sting operation” report, which revealed DTC companies giving misinformation and engaging in unethical practices, such as a company representative agreeing to test someone’s fiancé without that person’s consent.

Toward Realistic Expectations

What is in the near future for personalized medicine? Whether DTC genetic testing remains a force or proves

a passing fad, it seems inevitable that molecular profiling will become a more routine and familiar part of going to the doc-tor. It is likely to be used more frequently for preventive and therapeutic care. Two people with the same condition may get very different treatments, with genetic testing revealing variations in metabolism, allergies, and responsiveness to par-ticular medications and regimens. Recommendations for diet and exercise plans may vary. Dosing will be more precise to minimize side effects, and targeted treatments will likely be more effective and palatable than a standard trial-and-error approach.

But whether tailoring medical care to individuals will save money or make decision-making easier for doctors and pa-tients remains to be seen. Even though personalized medicine reduces the use of ineffective medications and the costs of adverse side effects, it will not necessarily lower the cost of drug development or health care. It will entail various drugs targeting different population segments, diagnostic tests pre-scribed alongside them, and complex clinical trials showing safety and efficacy within subpopulations. Physicians and pa-tients may also be uncomfortable or confused about relying on genetic tests if they lead to information overload or yield results that are ambiguous or inconsistent.

It is also unclear whether personalized medicine will be in alignment or at odds with comparative effectiveness research,

which gained prominence with health care reform. Critics fear that comparative effectiveness research could derail per-sonalized medicine with its focus on aggregating subsets of patients, perhaps at the risk of overlooking individuals or outliers. On the other hand, comparative effectiveness re-search has the potential to support personalized medicine by investigating how different populations respond to different interventions and honing in on patient subgroups that are especially likely to benefit from a treatment.

Care that is personalized is desirable in the broadest sense, recognizing the patient as a fleshed-out individual with a his-tory, relationships, values, and interests. It is both personal and personable. William Osler, the father of modern medi-cine, echoed Hippocrates’ focus on the individual when giv-ing care: “Care more particularly for the individual patient than for the special features of the disease.” Listening, evalu-ating, and responding to the patient to promote his or her in-terests is the foundation of clinical medicine. Using genetics to customize care, in whatever form that may take, could be a powerful tool to further refine the healing process.

T he phrase “personalized medicine” has a built-in pos-itive spin. Simple genetic tests can sometimes predict whether a particular individual will have a positive

response to a particular drug or, alternatively, suffer costly and debilitating side effects. But little attention has been giv-en to some challenging issues of justice raised by personalized

Personalized Medicine’s Ragged Edge

BY LEONARD M. FLECK

Leonard M. Fleck, “Personalized Medicine’s Ragged Edge,” Hastings Center Re-port 40, no. 5 (2010): 16-18.