An overly broad and scientifically problematic definition of genetic testing led the HHS Secretary's Advisory Committee on Genetics, Health, and Society to issue burdensome recommendations for regulating laboratory-developed tests, according to an article published by the medical director of a regional US diagnostics laboratory.
In its 276-page report on the oversight of genetic tests, released last April, SACGHS "used an overly broad definition of genetic testing that is neither scientifically sound nor practically workable," Roger Klein, medical director of molecular oncology at BloodCenter of Wisconsin's Diagnostic Laboratories, wrote in an article published in the February issue of Human Pathology.
Klein leads a program at his lab focused on DNA- and RNA-based testing for cancer patients, and is responsible for expanding the lab's menu of cancer diagnostics.
Among its recommendations, SACGHS suggested the following: "To help close the gaps in oversight related to clinical validity, which would help assure the appropriate use of laboratory tests, the FDA should address all laboratory tests, regardless of how they are produced (i.e., as a commercial test kit or laboratory-developed test), in a manner that takes advantage of its current experience."
In the report, the SACGHS defined a genetic or genomic test as that which is involved in the "analysis of human chromosomes, deoxyribonucleic acid, ribonucleic acid, genes, and/or gene products (e.g., enzymes and other types of proteins) … predominately used to detect heritable or somatic mutations, genotypes, or phenotypes related to disease and health" [see PGx Reporter 02-20-2008].
According to SACGHS, the purpose of genetic tests includes "predicting risk of disease, screening newborns, directing clinical management, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations."
SACGHS did not include in its definition tests used for forensic and identity purposes, as well as tests that are not considered genetic tests in the general population but may contribute to diagnosing a genetic disease or disorder. An example of the latter type of test is one used for cholesterol screening, which may reveal a genetic disorder such as an inherited form of hypercholesterolemia.
"This definition led to the Committee's inability to distinguish genetic tests from other complex laboratory assays," Klein concludes. As a result, the recommendation "has fallen short by unnecessarily advocating for FDA review of all laboratory developed tests and proposing the creation of a mandatory registry for all clinical laboratory tests."
In response to Klein's analysis, SACGHS clarified its position on federal oversight of genetics tests in an e-mail to Pharmacogenomics Reporter this week.
Sarah Carr, SACGHS executive director, emphasized that by recommending the "FDA should address all laboratory tests in a manner that takes advantage of its current experience in evaluating laboratory tests," the committee did not suggest the agency should review all LDTs.
"This approach would categorize tests based on risk; therefore, all tests would not need the same level of regulation," said the spokesperson.
A year ago, when SACGHS met to put the finishing touches on the draft version of its report on federal regulation of genetic testing, the committee felt that "applying the same regulatory framework to every genetic test is infeasible" from a time and cost perspective. However, at the time, the committee felt the FDA conduct "further analysis … to determine whether appropriate weight has been apportioned to risks associated with the novelty and complexity of the testing platform and technology."
However, the SACGHS report does not distinguish between complex LDTs and genetic testing in general.
"Although SACGHS was tasked to look at the oversight of genetic tests specifically, we concluded that the concerns associated with genetic testing generally do not differ from other complex laboratory tests," the committee acknowledged in its report. "For this reason, and because it will be increasingly difficult to distinguish between genetic and other complex laboratory tests, we chose to apply a number of our recommendations to laboratory tests generally."
This "generality" is the source of Klein's commentary, which stresses that the committee's use of the term "gene products" is too broad and scientifically problematic.
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"If the SACGHS definition is applied literally, it would encompass most laboratory testing performed for diagnostic purposes. The reason is that genes store most of the information used to create human beings," Klein told Pharmacogenomics Reporter. "In physical terms people are chiefly agglomerations of the 'gene products' included in SACGHS' definition.
Klein points out that since virtually all diseases are in some way the product of genetic interactions, SACGHS' definition makes it "impossible to draw lines between what is and is not 'genetic,'" which has the result of recommending that the FDA review most disease-related laboratory testing.
Responding to this assertion, the SACGHS spokesperson explained that the committee's use of the term "gene products" refers to the products of gene transcription, such as mRNA, and translation, including proteins and enzymes.
"Traditionally, newborn screening, which includes measurements for enzyme deficiencies, has been considered genetic testing. Also, gene-expression and protein-expression arrays are emerging as promising technologies for assessing health," Carr said in the e-mail. "In his charge to the Committee, the Secretary asked SACGHS to be forward-looking in its report, and the Committee thought it was important to consider these types of tests."
In Klein's view, SACGHS should have narrowed its definition of genetic diseases to focus on genetic variants predisposing to inherited diseases and to encompass assays performed for the detection of high penetrance hereditable predispositions.
SACGHS considers this proposal too narrow.
"SACGHS thought it was important to include testing for somatic mutations as, increasingly, tumor samples are analyzed to guide therapeutic choices; limiting the definition to inherited disorders would miss a substantial part of genetic tests important to the practice of modern medicine," Carr noted.
'Unjustified and Misguided'
Traditionally, the FDA has practiced "enforcement discretion" over most laboratory-developed tests, which are overseen by CMS. But when the FDA decided in 2007 it would regulate a more complex type of LDT called in vitro diagnostic multivariate index assays, test developers claimed that the resulting regulatory strategy would be inequitable, arbitrary, and that it would hinder innovation [see PGx Reporter 02-14-07].
Siding with those who are against FDA oversight of LDTs, Klein criticizes SACGHS' recommendations for FDA review of all laboratory tests and the creation of a mandatory Web-based registry for all LDTs as "unjustified and misguided.
"The imposition of an increased regulatory burden will raise the cost of diagnostic laboratory testing and decrease patient access to beneficial new assays," Klein concludes in the Human Pathology article.
SACGHS maintains, however, that genetic tests and diagnostic labs should be held to the same "high standards of accuracy, validity, and utility as other medical information" is subject to. "The Committee believes that a broad definition of genetic tests is appropriate and fine distinctions between genetic and other complex laboratory tests are not likely to be helpful from a policy perspective," Carr said.
Furthermore, with regard to cost burdens to the FDA, SACGHS "recommended that HHS convene a multi-stakeholder group, from the private and public sectors, to consider new and existing regulatory models, which should include a cost analysis of the proposed regulatory models," Carr added.
However, Klein characterizes the view that LDTs lack professional standards or oversight as "the most serious misconceptions among some policy advocates." Since most labs are accredited by the College of American Pathologists and many national laboratories have to gain New York State certification, Klein notes that these standards exceed CMS' CLIA requirements.
"The idea that the CLIA regulations reflect the actual level of oversight of genetic testing or represent the standards of molecular pathology practice in this country is unequivocally false," he told PGx Reporter.