Barriers To Genetic-Based Medicine

Imagine that researchers have discovered a genetic biomarker in some breast tumors that can help predict whether a woman will have a recurrence of breast cancer and, therefore, whether chemotherapy will be effective. Women who test positive for the biomarker would receive chemotherapy regardless of their other risk factors, and women who test negative would not. Such a treatment approach could save thousands of lives while sparing some women from the toxic side effects of chemotherapy. The situation is hypothetical, but it is one that oncologists and other physicians are grappling with as genetic testing and personalized medicine become more mainstream.

Two key issues have emerged from the debate over genetic-based health care. The first is the concern over patient privacy as more and more genetic data are generated and shared over the Internet. The second is the clamor for the Food & Drug Administration to regulate genetic tests to ensure that they measure what they say they do and that results are clinically meaningful.

Several events last month sparked discussion of questions surrounding genetic testing and personalized medicine. At a June 20 event convened by the American Association for the Advancement of Science (AAAS) and the Food & Drug Law Institute (FDLI), a panel of experts wrestled with the social, legal, and ethical implications of using individual differences in genetic profiles to assess susceptibility to disease, to predict whether a drug will have serious side effects, and to recommend lifestyle changes. The event followed closely on the heels of a June 10 policy seminar on personal genomics sponsored by the Johns Hopkins University Genetics & Public Policy Center (GPPC) and a June 12 roundtable discussion on genetic testing oversight held by the Senate Special Committee on Aging.

At the AAAS/FDLI event, the panel of experts kicked off the meeting by addressing the hypothetical breast cancer example. Although everyone agreed that the patient's health should be the number one factor in determining which treatment to use, reimbursement for the costs of genetic tests was a topic of great discussion. In general, insurance companies will pay only for services that will yield information that informs decision-making and improves health outcomes, said Joanne C. Armstrong, a senior medical director with the insurance company Aetna.

Insurance companies want evidence based on data from randomized clinical trials in the peer-reviewed literature that a test will improve a patient's health, Armstrong continued. They also consider how a test performs in the real world, whether standard procedures are followed during routine performance of the test, the reproducibility of the test, and interlaboratory variability of test results, she said.

From an ethics perspective, panelist Carol Isaacson Barash, principal of Boston-based Genetics, Ethics & Policy Consulting, brought up concerns about patient privacy. When society starts singling out people with a specific biomarker and distinct clinical features into a small subset of the population, privacy concerns become elevated, she said. These data may support funding requests for subsequent clinical research, and they may be shared globally via the Web, she added.

Because more data are being generated and shared, other panelists looked to the federal government to step in and implement an infrastructure to better track genetic information. "We have to be sensitive to privacy issues," cautioned Charles N. Rotimi, director of the Intramural Center for Genomics & Health Disparities at the National Institutes of Health. "We are generating lots of genetic data that are out in the public domain. Consumers now have the ability to get information in ways that doctors don't even know about."

Many people are advocating for a publicly available genetic testing registry to increase transparency of genetic tests so that consumers know exactly what a test measures. In the past few years, numerous direct-to-consumer genetic testing companies have sprung up, leaving consumers confused about what they are actually getting for their money. In 2006, GPPC estimated that eight Web-based companies were offering direct-to-consumer genetic testing for health-related conditions. Today, GPPC estimates that the number is closer to 30.

"There are a lot of direct-to-consumer tests out there, and they fall into a lot of different categories," said Henry T. (Hank) Greely, a bioethics law professor at Stanford Law School at the June 10 GPPC seminar. He explained that although some genetic tests are from well-established companies that provide an honest risk assessment of developing serious disease, others are from questionable companies that determine risk on the basis of findings from a single study. Still others, such as "DNA dating services that will fix you up with your ideal person based on your immune system alleles," are downright fraudulent, he said.

Direct-to-consumer genetic testing is in "a state of complete disarray," said Grail Sipes, a lawyer specializing in food, drug, and life sciences policy at Covington & Burling LLP, at the AAAS/FDLI panel discussion on June 20. "People are asking for tests they don't know the significance of."

GPPC estimates that genetic tests are available for more than 1,200 clinical conditions. Although these tests can't tell whether a person will get a particular disease, they do estimate that person's risk of getting that disease compared with the average person's. One common problem with these direct-to-consumer genetic tests is that they are marketed largely to healthy people and don't include any information from a genetic counselor or doctor to put the results in context, Kathy Hudson, director of GPPC, emphasized during the June 10 seminar.

The disparity among such genetic tests is the result of little government oversight, Hudson and others contend. Although FDA regulates test kits as medical devices to ensure that they are safe and that they measure what they say they do, most genetic tests are considered laboratory-developed tests, which are not subject to FDA regulation.

"Right now we have a fairly fragmented and complicated regulatory picture, with a limited number of genetic tests being subject to FDA oversight," Gail H. Javitt, law and policy director of GPPC, tells C&EN.

The difference between an FDA-regulated test kit and an unregulated laboratory-developed test has to do with how a test is produced, Javitt says. "If a laboratory produces a test in-house using various reagents and protocols that it develops to produce an end result, then the test would be considered a laboratory-developed test. If the lab purchased bundled reagents with instructions and labeling as a kit, the test would be considered an in vitro diagnostic medical device, which is subject to FDA approval," she explains.

"The vast majority of genetic tests are subject only to the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which is a laboratory quality statute that looks at the laboratory and not the test," Javitt notes. The quality of laboratory testing is regulated by the Centers for Medicare & Medicaid Services (CMS), which is part of the Department of Health & Human Services (HHS).

Although FDA currently does not regulate laboratory-developed tests, the agency has indicated that it will likely regulate some of them in the near future. In 2006, FDA developed a draft guidance document on a subsection of laboratory-developed tests called in vitro diagnostic multivariate-index assays. The agency defines these assays as those that involve multiple signals, use some sort of algorithm, and yield a patient-specific treatment-related result intended for use in diagnosis of disease or in treatment or prevention of disease. A genomic-health assay is the best example of such assays, Javitt says. The agency has a heightened level of concern about that kind of test and anticipates that more of them will be coming along. FDA has signaled to industry that it will regulate these assays, but such regulation is still in draft form, Javitt notes.

Various state laws have attempted to fill in the oversight gaps. For example, New York requires companies to demonstrate the clinical validity of their tests, which goes beyond the federal regulations. The State of California has also interpreted its laws to be more restrictive than the federal rules. In mid-June, California's Department of Public Health sent letters to 13 direct-to-consumer genetic testing companies asking them to demonstrate that they have a California license and that the tests they run for customers in California were ordered by a medical doctor, as required under state law. To get a California license, a company must show some validation of its test, which is more than the federal CLIA statute requires, Javitt notes.

Anticipating that demand for genetic testing will grow, the HHS Secretary's Advisory Committee on Genetics, Health & Society (SACGHS) has been looking into oversight of genetic testing since 2006. In April, SACGHS released a comprehensive report outlining some serious gaps in oversight and making recommendations to fill them.

In its report, SACGHS expressed concern about the lack of requirements for proficiency testing for genetic testing laboratories and recommended that if proficiency-testing programs exist, laboratories should be required to enroll in them. Proficiency-testing programs, which determine whether laboratories can get the correct answers with their test, do exist for about two dozen genetic tests, Javitt tells C&EN.

The report also recommended that FDA play a role in the oversight of genetic testing to ensure clinical validity and that the Federal Trade Commission be more aggressive in enforcing laws against false and misleading advertising by direct-to-consumer genetic-testing companies.

In Congress, Sen. Gordon Smith (R-Ore.) held a hearing two years ago related to genetic testing. Specifically, the hearing was based on concerns raised by a Government Accountability Office report (GAO-06-977T) about nutrigenetic direct-to-consumer tests. Such tests claimed to deliver personalized nutrition and lifestyle guidance from genetic material taken from a self-collected cheek swab.

Smith has continued to follow the issue. As ranking member of the Senate Special Committee on Aging, he held a roundtable discussion on the regulatory, scientific, and ethical issues of genetic testing on June 12.

At that discussion, Judy Yost, director of CMS's Division of Laboratory Services/CLIA Program, noted that CMS and the Centers for Disease Control & Prevention have been collaborating on a best practices guide for genetic testing labs. She also mentioned that CMS intends to update regulations to require some genetic testing labs to enroll in proficiency-testing programs.

To address the lack of regulatory oversight of genetic tests, two bills have been introduced in the Senate. One bill—the Laboratory Test Improvement Act (S. 736), sponsored by Smith and Sen. Edward M. Kennedy (D-Mass.)—would give FDA explicit authority over laboratory-developed tests. The other bill—sponsored by Sen. Barack Obama (D-Ill.)—the Genomics & Personalized Medicine Act of 2007 (S. 976), is a far-reaching bill that has a regulatory component. It calls for more coordination among federal agencies relating to genomic research, a national database of genomic information, and improved training for physicians and genetic counselors. Both bills were referred to the Senate Health, Education, Labor & Pensions Committee, but neither has seen any movement this year.

Most scientists believe that genetic testing will eventually become an integral part of health care. In a few cases, genetic profiling has already played a role in reducing adverse side effects, or in determining the proper dose, of drugs for various cancers and cardiovascular disease. And many more gene-based therapies are on their way.

Growing consumer demand for genetic tests coupled with the proliferation of commercial genetic tests is driving calls for more government oversight. As FDA moves to regulate some aspects of this testing area, congressional action will likely be needed to help manage the growth of this emerging health care issue.

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