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FDA Releases List of Evidence-Based PGx Variants

NEW YORK – The US Food and Drug Administration on Thursday unveiled a table of gene-drug associations for which it believes there is sufficient scientific evidence.

The list, compiled under collaboration between FDA's Center for Devices and Radiological Health and the Center for Drug Evaluation and Research, is intended to provide "the agency's view of the state of the current science in pharmacogenetics," Jeff Shuren, director of the agency device division, wrote in a statement.  

The online resource includes pharmacogenetic variants that are in FDA-approved drug labels, as well as gene-drug interactions that "are consistent with current FDA labeling and for which there is sufficient scientific evidence based on the published literature." The listed variants are divided into three categories: PGx associations with sufficient evidence to allow their use in guiding therapy management; associations with data to suggest a potential impact on drug safety or response; and associations with data demonstrating only an impact on pharmacokinetic properties. The third category, according to the FDA, lists variants for which the association between the genotype and drug safety or response has not been established.

The agency is asking stakeholders to submit comments in the Federal Register on the variants in the table.

Shuren acknowledgted that the table "is not complete," but that the agency still "felt it is important to provide clinicians, patients and test developers with information now while we continue to review the scientific evidence, including the scientific evidence underlying various professional guidelines, such as those of the Clinical Pharmacogenetics Implementation Consortium." The agency said it will update the online list of variants periodically, "as the evidence evolves."

The FDA has been prodding labs performing pharmacogenetic testing, and software firms providing reports from such testing, to undergo regulatory review. The agency issued a safety alert in October 2018, in which it called out unapproved PGx tests and software used to make clinical recommendations as a public health risk.  

The agency followed up this safety alert with a warning letter last April to Inova Health System's genomics lab for conducting PGx tests without its blessing. Then, over the summer, the FDA began calling up labs in this sector and asking them to remove any mentions of drugs associated with PGx variants in reports.

Some in industry pushed back, calling out the FDA's actions as lacking transparency and consistency. A group of stakeholders formed a coalition to ask the agency to stop attempting to shut down PGx labs and to make any new, substantive changes in regulations through notice-and-comment rulemaking, as required by law.  

In his statement announcing the availability of the online PGx variant list, Shuren noted that labs continue to market PGx tests with claims that lack sufficient evidence, and that the agency would continue to take action in instances where it feels the public health is at risk.

"Unfortunately, in the time since our safety communication was issued, some manufacturers of pharmacogenetic tests with claims not adequately supported by sound science have continued marketing their tests, including some for medications to treat seizures, mental illness and pain, including opioids," he stated. "The FDA remains concerned with the safe use of these medications based on pharmacogenetic test reports that are not supported by sound science."

Since most commercially available PGx tests are performed within single labs, and are therefore considered lab-developed tests, the agency's actions against such tests have been caught up in the longstanding debate around FDA's authority to regulate lab services. The FDA has said that it plans to continue to exercise enforcement discretion, while it works with stakeholders to advance a more modern regulatory system via legislation that addresses the broader use and marketing of LDTs today.

At the same time, the agency has also maintained its authority to regulate LDTs that put the public health at risk. "The FDA is committed to continuing to work with Congress on a broader legislative solution to the oversight of in vitro clinical tests generally (including LDTs), which would modernize our regulation of these tests," Shuren said. "In the meantime, the FDA should not and cannot stand idly by when safety issues arise."

The list of evidence-based gene-drug associations is one way FDA is hoping to strike a balance between maintaining patient access to PGx tests based on sound science and protecting public health.

"Consistent with our mission to protect and promote public health, we believe it is important to take steps now to help ensure that claims being made for pharmacogenetic tests offered today are grounded in sound science to avoid inappropriate management of patients' medications — and to do so through approaches that both protect patients and advance the development of analytically and clinically validated pharmacogenetic tests," Shuren said. "Indeed, genetic testing can enhance patient management by improving the selection of medications or the dosage of a medication, tailoring the therapy to the patient — but only when it is based on sound science."

Industry stakeholders had specifically criticized that in the FDA's safety communication and in its private discussions with labs, the agency was not providing clarity around what it considers evidence-based PGx variants: Were they only those variants in FDA-approved labeling? What about variants that are in guidelines from expert bodies, such as the Clinical Pharmacogenetics Implementation Consortium?

Leaders involved with CPIC have been in communication with the agency, and the FDA appears to have recognized the importance of consensus guidelines. Shuren said in his statement that because not all supported gene-drug interactions may be found in current drug labeling, the FDA compiled its list drawing on information from labeling and the published literature. "This literature-based scientific evidence is often used in support of the recommendations found in professional guidelines used by clinicians," he added.

Shuren said the agency is also exploring other strategies for evaluating the evidence on gene-drug associations, including via establishing a community-based collaborative approach.  

"We will continue to communicate about the promise and potential of pharmacogenetic testing, and about when we have concerns regarding claims that are not supported by sufficient scientific evidence," he said. "We are committed to engaging with stakeholders as we work to protect patients while fostering the development of new and innovative diagnostics."