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FDA Guidance on PGx Tests for Heritable Markers Does Not Say When 510(k), PMA Needed

A recently released guidance to industry and US Food and Drug Administration staff, called “Pharmacogenetic Tests and Genetic Tests for Heritable Markers,” is not explicit enough in outlining when diagnostic companies will need to apply for premarket approval and when a 510(k) clearance will be sufficient, according to a lawyer representing the interests of diagnostic companies, patient groups, and investors.
“The guidance is fairly general and does not provide a lot of guidance as to when a premarket approval application will be required versus a 510(k) clearance,” Paul Radensky, legal advisor to the Coalition for 21st Century Medicine, told Pharmacogenomics Reporter this week. The coalition, formed earlier this year, comprises genomic, proteomic, and molecular diagnostic companies, advocacy groups, and investors.
The guidance, as it is written, appears general in language and broad in scope. The agency states that the guidelines apply to pharmacogenetic and genetic tests, and although not specifically addressed, the principles in the guidance may also be applied to gene expression tests for non-heritable mutations, as well as tests based on other matrices such as protein-based tests “when the purpose is to provide genetic information,” FDA said.
According to the guidance, “the appropriate type of submission depends on claims and information regarding the specific device.” The agency said it expects most pharmacogenetic and genetic device submissions to fall under the traditional 510(k) or de novo classifications.
With this guidance the FDA lays out a framework for the types of information sponsors will need to submit for a PMA or a 510(k) application. “Although this document focuses on information to include in a 510(k), the general types of information are likely to be the same for PMAs,” the agency states in the guidance.
FDA said it might request different types of analyses for PMAs. The types of information the agency will require from sponsors will depend on the intended use of the device, the indication (predictive or prognostic, treatment response, or drug sensitivity), the methodology (i.e., PCR), the technical interpretation of results, assay limitations, performance, benefits and risks, clinical validity and interpretation, and the claims made by the manufacturers.
The agency maintains that its recommendations in the guidance are “purposefully” general.
“It is well-known that each testing system will have an associated unique set of concerns, and we expect to identify and discuss these unique concerns with individual manufacturers,” the agency said.
Still, according to stakeholders, the broad nature of the guidance may hold good news for laboratory developers of PGx and genetic tests for heritable diseases that are considered in vitro diagnostic multivariate index assays. Meanwhile, the FDA’s requirements for studies for rare markers may be too burdensome for sponsors, commentators on the guidance say.
FDA Oversight Beyond Test Kits?
For some, the general nature of the guidance suggests that FDA is leaving gaps in its oversight of certain types of genetic tests.
In comments to the draft version of the guidance, which was originally issued last February, Johns Hopkins University’s Genetics & Public Policy Center noted that the document largely concerns genetic test kits and does not explicitly deal with laboratory-developed tests.
“While the scope [of the draft] is appropriately broad regarding the type of genetic tests covered, it is unclear, and therefore potentially unduly narrow, regarding the context in which genetic tests will be subject to FDA’s 510(k) or PMA requirements,” the GPPC commented. “While never explicitly stated, it appears that the draft guidance is applicable only to diagnostic ‘test kits,’ i.e., freestanding diagnostic products that laboratories may purchase to perform genetic tests, and is not applicable to tests developed in-house by clinical laboratories.
“Assuming this is the case, FDA’s well-intentioned effort to ensure the quality of genetic testing likely will fall short of its goal,” the GPPC said. The GPPC concluded that these guidelines will have a limited impact on ensuring the safety of genetic tests if only applied to test kits under FDA jurisdiction, and not also to laboratory-developed tests.
Even though the final version of the guidance still seems to generally focus on genetic-test kits, and does not specifically discuss laboratory-developed tests, the makers of the latter type of test could still be impacted by this guidance.
Prior to FDA finalizing its guidance for a subset of lab-developed tests called in vitro diagnostic multivariate index assays, which it released as a draft last fall, laboratory test developers of PGx and genetic tests of heritable markers may choose to take their products through FDA under this current guidance and the application requirements may be less burdensome than under the IVDMIA guidance. However, it is possible that this subset of tests may fall under both guidances if FDA finalizes its IVDMIA draft guidance, and this may add confusion to an already complex regulatory issue.
If most pharmacogenetic and genetic tests can be submitted as 510(k) or de novo applications, then “this would be welcome as it appears under the draft IVDMIA guidance that tests used to predict treatment outcome are likely to require PMA,” Radensky said.
The coalition that Radensky represents was formed last fall around the time FDA issued the draft IVDMIA guidance to regulate laboratory-developed algorithm-based assays, which are currently under the purview of CMS’ Clinical Laboratory Improvement Amendments [see PGx Reporter 02-21-2007].
The 26-member coalition has asked the FDA to alter its plan to regulate IVDMIAs, arguing that if the guidance is implemented as drafted, “vital medical tests may become unavailable, innovation and improvements could be impeded, the cost of research and development could rise, and insurance coverage for laboratory tests could erode or disappear.”

If most pharmacogenetic and genetic tests can be submitted as 510(k) or de novo applications, then “this would be welcome as it appears under the draft IVDMIA guidance that tests used to predict treatment outcome are likely to require PMA.”

According to Radensky, since the guidance for PGx and genetic tests for heritable markers covers sponsors of in vitro diagnostics under FDA jurisdiction, and the IVDMIA draft guidance proposes an extension of FDA jurisdiction over a subset of laboratory developed tests, the two guidances are not directly related.
“Should a laboratory developing a pharmacogenetic [laboratory-developed test] or an LDT comprising a genetic test for a heritable marker choose to follow an FDA clearance/approval pathway, then this guidance would be relevant,” Radensky states. “Similarly, should FDA finalize the IVDMIA guidance or otherwise begin to enforce FDA jurisdiction over LDTs, then LDTs comprising pharmacogenetic tests or genetic tests for heritable markers would [also] fall under this guidance.”
According to Radensky, it is conceivable that “the two guidances may be confusing when read together in trying to understand FDA's assessment of risk and what level of controls are required to manage that risk.”
Large Studies to Test Rare Markers
Although the final guidance is general and broad, the FDA does specifically address testing for rare disorders to discourage sponsors from using enrichment designs.
For alleles, genotypes, and mutations that have a low prevalence in a given population “samples from many patients should be obtained in order to detect a significant number of positives,” the guidance states. For alleles, genotypes, and mutations that are prevalent in a particular ethnic group, patients from that group should “participate in the study in significant numbers.”
Although the agency acknowledges that enrichment designs might be appropriate in certain circumstances, it notes that the retrospective selection of subjects can impact the test’s sensitivity and predictive values.
In comments to the draft, a major point of contention among stakeholders was FDA’s treatment of genetic tests for rare diseases.
“Requirements for statistically significant data to demonstrate clinical validity become particularly burdensome if they are applied to markers associated with rare diseases,” Hoffman-LaRoche said in its comments.
Abbott pointed out in its comments to the draft guidance that without enrichment, a study for a rare mutation that occurs in one out of 5,000 people would require 50,000 patient specimens to obtain 10 positive specimens. “We encourage the agency to provide additional guidance in regards to a least burdensome approach to studies for rare disorders,” Abbott said.
Additionally, the agency warns that screening for rare markers may lead to false positives. “When many samples are tested for rare events, false positive results could become problematic in that they may be more common than true positives, due to test error and low prevalence,” FDA states.
Ultimately, while the FDA did respond to some concerns put forth by stakeholders to the draft, “it appears that many concerns remain unaddressed,” Radensky said.
The FDA recommends that sponsors submit their protocols to the agency before starting their studies, or submitting a 510(k) or a PMA. The agency directs sponsors to its “Guidance for Industry: Pharmacogenomic Data Submissions” or to the special controls documents for specific types of genetic tests for additional information regarding applications focusing on PGx tests and data.

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