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GPPC Calls for Improved Oversight of PGx Dxs After Uncovering Inconsistent Marketing

This article has been updated from a previous version to include comments from Seryx.
Researchers from Johns Hopkins University's Genetics and Public Policy Center last week said they uncovered inconsistencies and misleading claims made by companies selling CYP450 testing services designed to help guide treatments of certain antidepressants.
Their findings, which appeared last week in Science, come three months after a Centers for Disease Control and Prevention working group discouraged the use of such tests due to inadequate evidence that they provide useful information.  
After reviewing how genetic tests, such as Roche's AmpliChip, are used to guide treatment with selective serotonin reuptake inhibitors, the CDC’s Evaluation of Genomic Applications in Practice and Prevention Working Group in January “discourag[ed the] use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed."
Furthermore, the working group found that “in the absence of data that testing influences treatment or outcomes, there is a risk that the CYP450 test could increase costs without helping patients” [see PGx Reporter 01-08-2008].  
TheGPPC's Science paper concluded that there is “clearly a need for leadership at the federal level” to ensure that genetic tests marketed to the public are safe and efficacious.
In the study, GPPC Director Kathy Hudson and colleagues identified 15 companies marketing genetic tests for SSRI treatment, and four firms — Genelex, DNA Direct, Seryx, and Laboratory Corporation of America — that on their websites make scientific claims about the value of using genetic testing to dose or prescribe SSRIs, despite the fact that this value has not been clinically validated.
Writing in Science, the GPPC researchers said that “among the four websites surveyed, there were inconsistencies regarding which genes are genotyped for each of five SSRIs, a finding that shows the lack of consensus within the community as to what genes are relevant to test for each SSRI. This lack of consensus is likely confusing to both patients and doctors.”
According to that paper, entitled “A case study of personalized medicine,” a dearth in regulatory oversight of genetic tests by the US Food and Drug Administration and the Federal Trade Commission has created a marketing environment that can be potentially harmful to the public's health.
“Federal advisory committees, lawmakers, and stakeholders groups have made recommendations about enhancements in the oversight of genetic testing ... However, to date, the government has not taken meaningful steps to enhance the oversight of genetic testing,” the authors state.
To improve the regulatory situation, the authors suggest the FTC enhance its oversight of genetic testing companies making claims it believes to be misleading; the FDA should regulate the analytical validity of such tests regardless of the platform on which they are based; and genetic test manufacturers should submit their tests to a mandatory, publicly accessible, web-based registry.
Responding to industry and patient groups' suggestions for developing such a registry, the HHS Secretary’s Advisory Committee for Genetics, Health, and Society decided in February to mandate the development of a web-based registry designed to enhance the understanding and transparency of such tests [see PGx Reporter 02-20-2008].
Ahead of the SACGHS' decision to create the database, groups like the GPPC, Genetic Alliance, and the Coalition for 21st Century Medicine had been advocating for the FDA to create such a registry to collect data on a product for three to five years before deciding whether to subject that test to pre-market approval or 510(k) clearance [see PGx Reporter 02-06-2008].
“At this early stage of personalized genomic medicine, it is essential to be certain that regulatory infrastructure is tailored in a manner beneficial to public health,” the authors wrote.
The Survey
To conduct the survey of marketing claims made by genetic testing companies, GPPC's researchers conducted an Internet search to identify businesses offering CYP450 testing. “We reviewed their websites as a reasonable consumer would to see whether those businesses made any claims, explicit or implicit, regarding use of CYP450 testing for five SSRIs, and whether they appropriately cited scientific references,” Gail Javitt, GPPC's law and policy directory, told Pharmacogenomics Reporter this week.
“We evaluated the information on their websites in light of the findings of the EGAPP-commissioned evidence review and the EGAPP recommendations that followed,” she added.

“We agree that consumers should know as much as they can about their health, including disease risks, in order to make informed decisions and be their own best health advocate. For precisely this reason, information derived from genetic tests needs to be accurate and reliable and clearly relate to a person's health or risk of disease.”

The researchers looked at 15 companies offering services that either sell CYP450 tests or interpret test results with the goal of helping physicians better prescribe or dose Celexa (citalopram), Prozac (fluoxetine), Luvox (fluvoxamine), Paxil (paroxetine), and Zoloft (sertraline). They found that four such companies — DNA Direct, Genelex, Laboratory Corporation of America, and Seryx — include information about the relationship between CYP450 genetic testing and response to the SSRIs.
According to GPPC's analysis, LabCorp conducts the testing for DNA Direct and Seryx, while these two companies interpret the results for their customers. Genelex, on the other hand, both conducts the testing and interprets the results. DNA Direct and Genelex offer CYP450 testing direct-to-consumer, “rather than through a medical provider.”
According to the researchers, all four companies also sell CYP450 tests for other drug classes.
“Some websites make explicit claims about the utility of CYP450 testing for particular drugs, such as the claim by Genelex that pharmacogenetic testing is 'required to effectively prescribe Paxil,'” the GPPC cited in the Science paper. “Other websites are less direct, including information about SSRIs within tables that describe the relations between CYP450 genes and a number of different medications.”
GPPC isn't alone in its criticism of DTC genetic testing services. At a recent meeting of the HHS Secretary's Advisory Committee on Genetics, Health, and Society, some committee members expressed concern that the tests and claims made by such companies, including 23andMe, DecodeMe, and Navigenics, may not appropriately regulated by the FDA. Others fear that by giving patients their genetic data without appropriate counseling about what the information means, the doctor-patient relationship will be harmed.
Genelex's website warns consumers that “without knowing your genetics, your physician may need to go through months of trial-and-error prescribing to find the right drug and dose for you. ... Help your healthcare provider optimize your response to antidepressants and many other medications by ordering DNA testing.”
In response to the paper, Genelex CEO Howard Coleman issued a statement last week asserting that the text was quoted out of context.
“I think individuals have the right to learn their genotype,” Kristine Ashcraft, director of operations at Genelex, told Pharmacogenomics Reporter sister publication GenomeWeb Daily News last week.
Although Ashcraft acknowledged that there are no data from randomized trials that can confirm the value of CYP450 testing to guide SSRI treatment, there are studies currently underway that support the use of pharmacogenetic testing for such drugs. Ashcraft held that waiting on the results of these clinical trials could deny some individuals potentially helpful information, particularly for those who have had adverse drug reactions in the past.
Ashcraft said that without its direct-to-consumer efforts, patients would not get genotyped due to confidentiality concerns, which in turn would impede the adoption of DNA testing.
Similarly, DNA Direct issued a statement to the Science article, noting “inaccuracies” in the authors' analysis. “Katsanis, et al. suggests that DNA Direct provides CYP450 testing for SSRIs 'direct to consumer, rather than through a medical provider.' This is inaccurate. DNA Direct does not offer interpretation of CYP450 testing for SSRIs.
“DNA Direct is a web-enabled genetic consultation company staffed by board certified genetic counselors, with medical oversight provided by an M.D. medical geneticist,” the company maintained. “All medical genetic testing is provided according to standard medical guidelines developed under the oversight of our medical director.”
Furthermore, DNA Direct pointed out that it was not going against EGAPP's recommendations by marketing CYP450 testing directly to consumers, since the group concluded “there is insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment.” 
Seryx, describing itself as a "company that provides educational material to physicians as it relates to selected medications and CYP450," also had issues with the Science article. In a statement to Pharmacogenomics Reporter, Seryx said that its "service and reports were reviewed by FDA's [Office of In Vitro Diagnostic Device Evaluation and Safety] in 2007."

Furthermore, the company maintains that the information in provides to physicians "comes directly from the peer-reviewed literature, [and] is presented in a completely transparent fashion with full reference lists.

"We want to emphasize that our CYP450 interpretive service and reports are not marketed DTC," the company stated. "Our marketing efforts are aimed at physicians and healthcare professionals."

Javitt told Pharmacogenomics Reporter that GPPC is advocating for increased oversight of these tests precisely because people have a right to dependable and accurate information about their genes.
“We agree that consumers should know as much as they can about their health, including disease risks, in order to make informed decisions and be their own best health advocate,” Javitt said. “For precisely this reason, information derived from genetic tests needs to be accurate and reliable and clearly relate to a person's health or risk of disease. The benefits and limitations of a test also need to be appropriately explained to consumers within the context of their non-genetic risk factors.
“Companies should meet these criteria if they are going to offer testing,” she added.
Lacking Regulations
In the Science paper, the GPPC researchers assert that the FDA and the FTC, regulatory bodies that are already responsible for ensuring the safety and effectiveness of other commercial products and services, must oversee DTC genetic tests as well.
For instance, the FDA regulates genetic test kits but not all laboratory-developed tests. Most LDTs fall under the purview of the Centers for Medicare and Medicaid Services' Clinical Laboratory Improvement Amendment, under which labs do not have to show clinical validity of their tests for certification.
In addition, although the FDA reviews whether a test accurately detects the genetic variants it claims to, it does not require the company to prove that their tests are efficacious for a specific indication.
“In the case of Roche's AmpliChip test ... the intended use cleared by the FDA does not refer to any specific drug, but rather states that information about CYP2D6 and CYP2C19 genotypes 'may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized' by products of these genes,” according to the Science paper.
“Although FDA could, in theory, require manufacturers to demonstrate a test’s efficacy for a specific intended use (e.g., CYP450 testing for fluvoxamine) as a condition of test approval, the agency instead has cleared CYP450 tests without clinical studies demonstrating that using these tests is beneficial in the selection or dosing of any particular SSRI,” the study added.
At the Molecular Medicine Tri-Conference in San Francisco last month, Steve Gutman, director of the FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, said that SACGHS would issue a report containing more than 200 pages of recommendations. He said the forthcoming guidelines “will be challenging for HHS to address.”
Pharmacogenomics Reporter sister publication GenomeWeb Daily News reported at the time that Gutman had said it is currently too early to say how much more of a role the FDA will play than it currently does in regulating genetic tests.
The Science paper also criticizes the FTC for allegedly failing to regulate the claims made by DTC genetic testing companies, which the authors claim is the agency’s responsibility. 
“In July 2006, in response to a US Government Accountability Office investigation and subsequent Senate hearing on the value of genetic tests sold directly to consumers, FTC issued a consumer alert publicizing the questionable claims made for some DTC genetic tests,” according to the Science paper. “This indirect approach has had no apparent effect on the availability of tests with questionable clinical validity.”
In the paper, the authors suggest that both the FDA and FTC enhance their oversight efforts over genetic tests, and that healthcare stakeholders develop a genetic testing registry to improve the transparency of these products.
The authors suggest that the FTC “use data analysis generated by EGAPP and others to take decisive action against companies making false or misleading claims about the benefit of genetic testing.” In addition, the FDA should expand its oversight by ensuring the accuracy of a test in gauging a specific drug response in a particular disease indication. Furthermore, the agency should ensure the safety and efficacy of all genetic tests, and not just limit its review of tests based on the platform used by the laboratory. 
Finally, the study recommends developing a genetic testing registry that “would aid doctors and patients in test selection and interpretation and afford a degree of transparency that currently is absent from the genetic-testing marketplace.”
Although the SAGGHS has mandated that such a registry will be developed, details about what types of information companies will be required to submit, which agency will have legal authority to oversee it, and the resources that will be required to develop and maintain it, have yet to be ironed out.
According to Javitt, there is “clearly a need for leadership at the federal level” to ensure that genetic tests marketed to the public are safe and efficacious.
“I hope our paper is a further step toward helping the agencies understand the magnitude of the problem and the need to work together to ensure the success of personalized medicine,” she added.

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