Aiming for a checks and balances system on pharmacogenetic tests, two U.S. Food and Drug Administration (FDA) centers have collaborated on a website that lists genetic variants known to affect drug therapies, and they’ve invited public comment about pharmacogenomic associations that should or shouldn’t be on the list. Through this tool, FDA’s Center for Devices and Radiological Health (CDRH) and Center for Drug Evaluation and Research (CDER) outline FDA’s current views of established gene-drug interactions that appear in its drug labeling approvals, in addition to gene-drug interactions that reflect current science and align with current FDA labeling protocols.

The web tool describes associations between certain genetic variants, or genetic variant-inferred phenotypes and altered drug metabolism. In certain instances, it lists differential effects such as variances in adverse event risk. Three comprehensive lists address pharmacogenetic associations for which the data support:

  • Therapeutic management recommendations.
  • Indicate a potential impact on safety or response.
  • Demonstrate a potential impact on pharmacokinetic properties only.

For example, individuals whose CYP2D6 polymorphism makes them poor metabolizers of amphetamine are at risk for adverse reactions. The FDA document advises clinicians to either lower the starting dosage or use an alternative agent. This is a clear case in which the data support a therapeutic management decision. Conversely, the beta-blocker carvedilol’s tendency to cause dizziness in patients whose CYP2D6 polymorphism causes them to metabolize the drug poorly is an instance in which the data show a potential impact on safety or response.

Sound scientific evidence must support any relationship between the gene variant, diplotypes, and the affected subgroup, and the claimed gene-drug interaction and affected subgroup. “FDA recognizes that practitioners will take into account different sources and strengths of evidence and will make prescribing decisions based on their judgment about which treatments are appropriate for individual patients,” the agency stated.

Pharmacogenetic testing shows some benefit as far as helping patients decide on a certain medication and the dosing amount,

CDRH and CDER directors Jeffrey E. Shuren MD, JD, and Janet Woodcock, MD, said in a statement. “When there is sufficient scientific evidence demonstrating a relationship between how a person’s genes may impact their metabolism of a drug or how they may respond to the drug, this information can be useful for health care providers,” they stated. The downside is the scientific evidence needed to support these tests for guiding prescribing decisions is insufficient. FDA warned the public about this shortcoming in a 2018 safety communication.

Nevertheless some manufacturers of pharmacogenetic tests continue to market their tests with unsupported claims, including some high-risk therapies such as opioids, according to Shuren and Woodcock.

Many of these tests are offered as laboratory developed tests (LDTs), which do not currently fall under FDA’s premarket review process. For many years, the agency has pushed for increased oversight of these tests through FDA channels. The agency is continuing to work with Congress on this matter, said Shuren and Woodcock. “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.”

AACC has long advocated against over-regulating LDTs. The tests fill important gaps in areas where current tests don’t meet clinical needs, the group contends. With the exception of certain high-risk tests that need dual oversight by FDA and the Centers for Medicare and Medicaid Services (CMS), AACC maintains that LDTs should remain under the purview of CMS via CLIA’88, which enforces stringent standards.

FDA plans to review and update its website as needed. “FDA recognizes that various other pharmacogenetic associations exist that are not listed here, and this table will be updated periodically with additional pharmacogenetic associations supported by sufficient scientific evidence,” the agency stated in its document. Stakeholders can provide feedback via FDA docket FDA-2020-N-0839.