American Association for Clinical Chemistry
Better health through laboratory medicine
January 2008 Clinical Laboratory News: Genetic Testing Oversight

January 2008: Volume 34, Number 1

Genetic Testing Oversight  
Is More Regulation Needed?
By Phil Kibak

As far back as 1997, a task force created by the National Institutes of Health–Department of Energy Working Group on Ethical, Legal and Social Implications of Human Genome Research suggested that CLIA requirements were inadequate to ensure the overall quality of genetic testing because they were not specifically designed for emerging molecular genetic tests. Now, a decade later, the adequacy of the current regulatory oversight of genetic testing has again been called into question by the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS), a group that provides policy advice to the Department of Health and Human Services (HHS) on the broad array of complex medical, ethical, legal, and social issues raised by the development and use of genetic technologies. In November, the group released a draft report with new recommendations regarding government oversight of genetic testing in which members concluded that there are significant and potentially harmful gaps in the current system. The report urges the HHS Secretary to take steps that would enhance interagency coordination of the activities associated with the oversight of genetic testing, including policy and resource development, education, regulation, and knowledge generation.

But this recent criticism of the current federal oversight of genetic testing in clinical labs may be more of the same. Responding to a 2006 petition filed by the Genetics and Public Policy Center, Public Citizen, and the Genetic Alliance calling for the agency to strengthen standards for genetic testing laboratories, CMS wrote in August 2007 that there was insufficient evidence to establish a new genetics specialty under CLIA. The agency said it will continue to vigorously apply existing quality control and other CLIA requirements to genetic testing and monitor further developments in the field of genetics.

“The people who direct clinical laboratory services seem to be in agreement with us that the existing regulations are adequate and that there is nothing unique about genetic testing that requires more than what we already have.” explained Judy Yost, Director of Division of Laboratory Services for CMS. “I think that when it comes to the regulatory environment, there will always be a pro group and a con group. But CMS will work with the genetic testing community to enhance oversight using our existing authority and mechanisms under CLIA.”

Specific Recommendations

But SACGHS isn’t satisfied with CMS’s response. The committee also recommended that expanded efforts are needed to prevent laboratories from performing genetic tests without appropriate CLIA certification. To resolve the problem, the group suggested that HHS explore mechanisms for developing new authorities and resources that will allow CMS to strengthen its enforcement efforts against laboratories that do so.

CMS already has at least one safeguard in place to ensure that laboratories involved in testing human specimens are enrolled in CLIA. Via Medicare and Medicaid, CMS denies payment to any laboratory that lacks an appropriate CLIA certificate and requests payment. CMS also will follow up, as a complaint, any information it receives about entities that perform testing without a CLIA certificate. CMS has pledged to work with the genetic testing community to identify entities that are not enrolled in CLIA and will provide materials to facilitate compliance for those not aware or familiar with current regulations. “We can inform those who prove to be resistant to compliance that they may be reported to the Inspector General [of HHS],” noted Yost.

SACGHS also criticized the CLIA requirements for proficiency testing and recommends that HHS fund studies to determine the effectiveness of other types of performance assessment methods to determine if they are as robust as proficiency testing (PT). However, at the November 2006 SACGHS meeting, Yost said CMS was committed to working with professional associations to develop consensus guidelines on molecular and genetic testing and that the agency plans to work with professional associations, the CDC, and the FDA to develop additional or alternative PT mechanisms for genetic testing. One avenue CMS had hoped to take was to work with the Clinical Laboratory Standards Institute or other professional organizations to develop some professional standards for genetic testing that the agency could incorporate into its surveyor guidelines. In addition a PT Workgroup—which is part of CDC’s larger effort to define best practices in laboratory medicine—is currently soliciting comments on the effectiveness of current PT programs, including genetic testing.

SACGHS also suggested that CMS update its list of regulated analytes to include genetic tests for which PT products are available and that HHS develop incentives for PT providers to expand their products for those tests. SACGHS further noted that there is a need for additional training of CLIA laboratory inspectors to enhance their understanding of the technologies, processes, and procedures used by genetic testing laboratories and to better equip them to assess compliance with CLIA requirements. In response, CMS has initiated discussions with the CDC, its CLIA partner, to design a process to update the listing of regulated analytes requiring PT in the CLIA regulations.

Yost said that some of the new SACGHS recommendations will require resources that the agency currently lacks. “Unfortunately,” she noted, “there are often boundaries to enhancing oversight, namely economics and resources. Many of the SACGHS recommendations involve additional funding and resources, and the source of these will be difficult to identify.”

However, CMS is implementing a multifaceted action plan designed to address the gaps, and SACGHS agrees that gaps can be addressed without creating a genetic testing specialty. “We’ve recently provided two sessions of genetics training to our surveyors to ensure they’re familiar with the latest technology and know what to look for,” said Yost. “But as far as expanding authority, that has to come from Congress. And we’re not sure we have the legal authority to oversee certain things. Those tests that may be lifestyle-oriented—for example, gender identification of a fetus, so the parents know whether to paint the nursery blue or pink—are information oriented but not health related, so that falls outside our scope.”

David S. Wilkinson, MD, PhD, Professor and Chairman of the Department of Pathology at Virginia Commonwealth University School of Medicine (Richmond, Va.) said the CLIA 1988 standards apply to genetic testing in the same way they apply to all other clinical laboratory testing to diagnose and manage human disease. “These requirements, if properly applied and enforced, are adequate to ensure safe and effective genetic testing. The field is moving rapidly and new tests are developed faster than the providers of PT can keep up with, so laboratories have to be diligent about using alternative PT approaches.”

And not all organizations involved in genetic testing believe that substantial change is needed. “It seems that some of the groups that have been pushing for a genetics testing specialty—for example, the American Clinical Laboratory Association —have come around to the CMS view that it’s a matter of working with what we have instead of trying to create something new for clinical testing, which is already covered in many respects by CLIA,” said Joe Boone, PhD, Acting Director of the Division of Laboratory Systems at the U.S. Centers for Disease Control and Prevention (CDC). “People are coming around to treating genetic testing for clinical purposes as no different from any other kind of clinical laboratory operation.”

This not just a U.S. issue either, he added. “Genetic testing has introduced a number of new twists into the oversight process that we didn’t have to consider before. For example, we have what may be as much as 25 percent of U.S. samples for rare genetic conditions going to genetic testing laboratories in other countries because the tests are so specialized.”

Booming: Direct-to-Consumer Genetic Testing

One of the reasons SACGHS committee members may have taken aim at regulation of genetic testing again is that a number of companies in the U.S. and abroad are going directly to the consumer with offers of confidential testing. But questions surround the oversight of such laboratories conducting tests designed to assess information that can be harvested from human genetic material. In November 2007 two firms— deCODE Genetics (Reykjavik, Iceland) and 23andMe (Mountain View, Calif.)— announced they were offering consumers a chance to find out information about their own genomes. For about $1,000 customers receive information based on genetic material from a mailed-in cheek swab or in a saliva-collecting tube. For the deCODE Genetics service, DNA extracted from the samples is compared against a database of other peoples’ genomes and a list of genomic variations that the company says, “are known to be associated with an above or below average risk of certain common diseases.” The 23andMe product works in a different fashion—outsourcing the analysis to Illumina (San Diego, Calif.), DNA extracted from the saliva sample is exposed to a genotyping platform that reads single nucleotide polymorphisms (SNPs). The data is returned to 23andMe, which analyzes the data and constructs a genome profile. Both companies insist that they provide information, not genetic testing.

Navigenics (Redwood Shores, Calif.) also will be entering the fray, with a test the company says will be available early this year. The company says it will help people understand their genetic predisposition to disease and arm them with information about what actions to take to help them stay healthy. To earn its $2,500 fee, the company says it will accomplish this initially through use of a saliva-based, whole genome scan and analysis, matching an individual’s DNA against scientifically and clinically vetted gene-disease correlation studies. The company’s home page proclaims, “Our lab is certified under CLIA, the law covering accuracy and timeliness of test results.”

The latest company to enter the direct-to-consumer market is Knome (Cambridge, Mass.), which says it will offer whole-genome sequencing for the lofty price of $350,000. Knome says its team of geneticists, clinicians, and bioinformaticians also will provide continued support and counseling.

Emily Winn-Deen, PhD, Vice President of Strategic Planning and Business Development with Cepheid (Sunnyvale, Calif.) and a member of SACGHS, thinks regulatory oversight of these companies depends on what they claim they’re doing. “If consumers who purchase these services are supposed to make healthcare decisions based on the information they receive from these companies, or are supposed to take this information to a physician, then, in theory, these companies should be CLIA-certified and I suspect the Centers for Medicare and Medicaid Services (CMS) will be looking at their claims.”

But it also depends on what the consumer is supposed to learn from the DNA sequence information that these companies say they can provide, she added. “For a lot of the information these companies are gathering there is no application to disease, but they are building DNA files. I think these and other companies with similar products are being watched very carefully by CMS, the Food and Drug Administration, and the Federal Trade Commission to see if they step over the line into the practice of medicine. In my opinion, if people are having genetic tests done for the purpose of disease diagnosis or prognosis, it should be in the context of a healthcare practitioner or setting.”

Much also depends on what the consumer-directed information reported by these companies actually says, noted Boone. “The testing being conducted in the laboratory may be analytically quite sound, but the information the consumer gets may not be individually tailored. With regard to a nutrigenomic analysis, persons may receive a broad statement on a healthy diet, similar to what they could obtain from the CDC or they might be encouraged to purchase dietary supplements.”

FTC’s Role in Genetic Testing

The Federal Trade Commission (FTC) is the federal agency charged with preventing fraudulent, deceptive, and unfair business practices and enforcing truth in advertising. Genetic testing has recently hit the agency’s radar screen due to the growth in the number of laboratories marketing their tests directly to consumers via print and electronic publishing.

In July 2006, the FTC issued a “Facts for Consumers” on direct-to-consumer (DTC) genetic tests. The document says that “…some of these tests lack scientific validity, and others provide medical results that are meaningful only in the context of a full medical evaluation.” It also states, “…genetic tests should be performed in a specialized laboratory, and the results should be interpreted by a doctor or trained counselor who understands the value of genetic testing for a particular situation.”

The document also warns consumers that at-home genetic tests are not suitable substitutes for a traditional healthcare evaluation, which includes conventional laboratory tests like blood chemistry and lipid profiles. It further states that no at-home genetic test has been reviewed by the FDA and that the FDA has not reviewed the accuracy of their claims.

To see a copy of the document, go to the FTC Web site.


Proficiency Testing Still a Target

In September 2006, the journal Nature Biotechnology published a survey showing that many genetic laboratories were not performing PT on some of the genetic tests they offered (Nat Biotechnol. 2006 Sep;24(9):1083-90). The 65-question survey also indicated that laboratories that conducted PT for every test they offered experienced the fewest errors. Kathy Hudson, PhD, Director of the Genetics and Public Policy Center, led the study, in which laboratory directors responded to inquiries about the types of tests they performed, the volume, estimated number of errors and types of errors, and whether and what kinds of PT were performed in their labs.

Using the GeneTests Clinic Directory, the researchers identified 680 potential participants. A total of 190 were eligible based on the following criteria: the person completing the survey had to be the director of a molecular or biochemical testing laboratory that reported test results to patients or providers; directors of laboratories that tested only for paternity, identity, ancestry, cytogenetics, infectious diseases tissue typing, or newborn screening were not asked to participate. The survey captured information about the laboratory setting; whether the laboratory performed molecular or biochemical testing, or both; the qualifications of the laboratory director; laboratory accreditation and certification; test volume and menu; quality control practices; the nature and frequency of laboratory errors; and PT practices.

The survey found that many laboratories are not performing PT for all their tests; laboratories that did not perform some type of PT on all their tests were 8 times more likely to report multiple deficiencies compared with laboratories that did perform PT. Even when formal PT programs are available, some laboratories do not participate. Twenty-three percent of respondents stated their laboratories do not always perform PT using some other mechanism when a formal PT program is not available. Meanwhile, genetic testing laboratories are not always certified in other areas—about one-third of high volume laboratories and those with large testing menus had no specialty certification.

“There’s been an explosion in our understanding of the genetic basis of disease and in molecular and biochemical genetic testing,” said Gail Javitt, Law and Policy Director with the Genetics and Public Policy Center. “However, the CLIA regulations have not kept pace so we have repeatedly voiced our concern that CLIA needs to require that laboratories engage in PT to ensure they are getting analytically valid answers. CMS should require that genetic testing laboratories engage in available PT programs in the same way they require it for laboratories performing other high complexity tests.”

But PT is not the whole story, said Yost. “There is no question that the current listing of tests requiring PT under CLIA is outdated, since it was developed in 1992. There are thousands of tests a lab can conduct and only 83 require PT. If every test conducted by a laboratory needed to undergo this process, the cost would be prohibitive, especially for small labs,” she explained. “But under CLIA there is a backup requirement—if a lab doesn’t perform PT on a test because it’s not required by CLIA, twice a year the lab has to evaluate that test in some way to ensure it’s accurate. For example, the lab can split a specimen in half and send one piece off to another lab that performs the same test in the same way, and then compare the results. When we conduct lab inspections we look for that sort of thing and will issue a citation if the lab doesn’t do it or doesn’t do it correctly.”

Boone noted that “For some genetic tests there really is no material that can be distributed that is suitable for use in PT. The field hasn’t matured to the point where it can support PT for all the things people would like to have.”

CLIA is a package deal— it’s not just PT, Yost added. “People talk about PT because it’s measurable and it’s an outcome measure of quality. But those who focus on PT are not looking at the whole picture, which includes all the CLIA quality standards.”

Next Steps for SACGHS

SACGHS released the draft report for public comment on November 5 and notified the health and science community through a variety of mechanisms—the SACGHS Web site, the Federal Register, a “Dear Colleague” letter via a listserv with more than 2,000 addresses, and word-of-mouth—that comments would be accepted through December 21. “We were looking for input from a variety of sources, such as consumer groups, health professionals, professional societies, providers, payers, industry, laboratory groups, and advocacy organizations,” said Andrea Ferreira-Gonzalez, PhD, Professor of Pathology and Director of the Molecular Diagnostics Laboratory at Virginia Commonwealth University (Richmond, Va.), and Chair of the SACGHS Genetic Oversight Task Force.

At the close of the comment period, SACGHS members will consider the public comments and revise the report to reflect relevant input. SACGHS will meet again February 12–13 to discuss the revised report and make further changes to include appropriate information. The recommendations will be submitted to the Secretary of HHS on February 29 and a final report will be submitted to the Secretary on April 30.

For More Information

  • Additional information about the SACGHS meeting and report can be viewed at NIH SACGHS.
  • CDC Ponders Proficiency Testing Updates, Clinical Laboratory News, Vol. 33, No. 4, April 2007; on the AACC Web site.
  • An NIH-funded Web site estimates that today almost 1,500 genetic tests are available,