Developers of pharmacogenetic tests cheered in August when United Healthcare (UHC) concluded in a policy statement effective October 1, that “the use of pharmacogenetic multi-gene panels to guide therapy decisions is proven and medically necessary for antidepressants and antipsychotics” when all of three criteria are met:

  • The individual has a diagnosis of major depressive disorder or anxiety;
  • The individual has failed at least one prior medication to treat their condition; and
  • The multi-gene panel has no more than 15 relevant genes.

But this news has been significantly dampened for pharmacogenomic (PGx) developers as over the past year as the FDA has cracked down on laboratory developed tests (LDTs) and other pharmacogenetic tests that reference specific drugs or drug classes unless they have been approved agency.

“Bottom line: There remains considerable uncertainty in the pharmacogenomics landscape,” Piper Jaffray & Co. analyst William R. Quirk, CFA, wrote in a September 24 note to investors.

Jeffrey Shuren
Jeffrey E. Shuren MD, JD, director, CDRH

The FDA’s enforcement initiative began October 31, 2018, with a “Safety Communication” by the agency’s Center for Devices and Radiological Health (CDRH) and Center for Drug Evaluation and Research (CDER). The safety communication warned patients and healthcare providers not to change patient medication regimens based on results from genetic tests claiming to predict a patient’s response to specific medications, but which are not supported by scientific or clinical evidence.

“We have so much more to learn about the use of these tests for specific medications, what the results mean, and how we can apply the information to improve a patient’s health,” CDRH Director Jeffrey E. Shuren MD, JD, stated. “While we are committed to supporting innovation in this area, we will also be vigilant in protecting against the potential risks. We will continue to closely monitor this area and take appropriate enforcement action as necessary.”

“Significant public health concerns”

Six months after its safety communication, the FDA issued a public warning letter to Virginia-based Inova Genomics Laboratory, a division of the Inova Translational Medicine Institute. The agency accused Inova of illegally marketing its MediMap pharmacogenetic tests, since they had not been reviewed by the FDA for safety and effectiveness.

“These tests pose significant public health concerns as inaccurate test results could impact the decision-making of healthcare providers and patients in ways that are seriously detrimental to patient health,” the FDA contended in its warning letter, addressed to Inova Genomics Laboratory Director Ramaswamy Iyer, PhD by Timothy T. Stenzel, MD, PhD, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health.

PGx Pharmacogenomic Testing
Since late last year, the FDA has been cracking down on pharmaco­genomic testing both by test developers and by health systems like Inova, saying they have not provided documentation that their tests are supported by scientific or clinical evidence. [Genomind]

Inova initially told Clinical OMICs it promptly responded to the FDA’s letter, and defended the MediMap tests, citing FDA’s policy of enforcement discretion for LDTs. Two weeks later, Inova halted its MediMap tests.

“We have not resumed any testing,” Inova spokesperson Kelly Schlageter said October 8 in a statement. “We will let others continue to develop the full potential of genomic testing while we devote our energies to becoming among the leading health systems in the nation with an unwavering commitment to clinical excellence.”

The FDA expressed satisfaction with Inova’s response. “Based on our evaluation, it appears that you have addressed the violation(s) contained in this Warning Letter,” Stenzel wrote to Inova on May 31.

The FDA’s enforcement stance “shows their position that pharmacogenomic tests should be based on the available scientific evidence,” said Teri E. Klein, PhD, co-principal investigator and director of PharmGKB, a pharmacogenomics knowledge resource that encompasses clinical information including clinical guidelines and drug labels, potentially clinically actionable gene-drug associations, and genotype-phenotype relationships. PharmGKB collects, curates, and disseminates knowledge about the impact of human genetic variation on drug responses.

Klein, who is also a professor in the Departments of Biomedical Data Science and Medicine at Stanford University, said the FDA’s position “is strongly supported by PharmGKB and the pharmacogenomics community more broadly.

“There has obviously been a lot of discussion within the pharmacogenomics community as members try to interpret what the FDA’s actions mean for their own organization, whether they’re a testing company or a healthcare provider implementing pharmacogenomics in their clinics,” Klein said. “At the moment, the FDA have only cited their own resource, FDA-approved drug labels, as an acceptable source of pharmacogenomic information. There hasn’t yet been any mention—positive or negative—about external resources such as PharmGKB.”

“Wrong direction”

Among the companies affected by the FDA enforcement stance is Genomind. Over the summer, the FDA directed the King of Prussia, PA-based PGx test developer to remove information about medications in its reports on pharmacogenomic tests carried out through the company’s Professional PGx Express test (formerly called Genecept Assay until it was re-branded and re-launched in August). The test examines 24 key genes associated with mental health—information that, along with medical history, can help clinicians determine whether a drug will be an effective treatment for their patients.

“It seemed that [the FDA’s] actions had taken precision medicine in the wrong direction,” Genomind CEO Shawn Patrick O’Brien told Clinical OMICs.

In September, however, the FDA allowed Genomind to restore the medication information in reports to physicians. At deadline, patient reports continued to omit the information on specific medication names and classes, furnishing gene-only information instead.

PGx Test
Source: Genomind

O’Brien said the partial reversal followed months of dialogue between Genomind and the FDA that began soon after he became CEO in October, 2018. He said Genomind has informally submitted data to the FDA on the Professional PGx Express and a new test announced October 8, the CORE Anxiety and Depression Report—a 15-gene panel specifically designed for the pharmacogenomics of medications commonly used to treat anxiety and depression.

“Our expectation would be a de novo 510(k) application,” O’Brien said, referring to a premarket submission made to the FDA with the intent of demonstrating that a device to be marketed is at least as safe and effective or “substantially equivalent” to a legally marketed device not subject to premarket approval.

O’Brien said Genomind launched its CORE Anxiety and Depression Report on October 1 in response to UHC’s decision to cover PGx testing for a subset of depression and anxiety patients. As with Professional PGx Express, the company will not include medication references on CORE reports made available to patients.

“There’s been no clearance by the FDA of any tests at this point,” O’Brien said, “Keep in mind that there is no system right now at the FDA for a policy to approve these tests. I’m not going to speculate how they’re going to go forward. We’re trying to work with CDER to get a policy in place.”

Two industry stakeholder associations and four mental health advocacy groups have also weighed in on the FDA crackdown.

In September, The Association for Molecular Pathology (AMP) published a position statement for pharmacogenomic testing that spells out “best practices” criteria for laboratories to follow. AMP recommended that labs report drug-gene associations that are “robust and supported by strong scientific evidence in the peer-reviewed literature, in the FDA-approved drug label, and/or in clinical practice guidelines.”

AMP said pharmacogenomics test reports should include a statement of a patient’s metabolizer status as determined by the genotype and a list of the drugs that may be impacted by this genotype, as well as alternative dosing or treatments that doctors may consider. Patients should discuss their pharmacogenomics test result with their healthcare provider to determine if changes to their medication plan are warranted.

Supporting best practices

Among test developers supporting AMP’s “best practices” statement is Myriad Genetics. Its GeneSight Psychotropic Test is a laboratory-developed pharmacogenomic test designed to measure and analyze clinically important genomic variants in treating psychiatric disorders.

“As a laboratory developed test (LDT), Myriad is regulated by CLIA and has received all appropriate approvals as well as CAP accreditation,” Myriad spokesman Ron Rogers said. “In addition, GeneSight has undergone multiple successful reviews by New York State, which is an accredited third-party reviewer by the FDA.”

In addition to UHC, GeneSight is covered by Medicare, CareFirst, and Kroger Health. “We have ongoing conversations with other health plans,” Rogers said. “Payers and providers have consistently noted that they are most interested in improved remissions rates.”

Julie Khani
Julie Khani, president, ACLA

Also in September, American Clinical Laboratory Association (ACLA) President Julie Khani sent a letter to FDA Acting Commissioner Ned Sharpless, MD, urging the FDA to halt its enforcement initiative, and instead encourage “responsible” LDT development by adopting recommendations such as those offered by professional groups, and formally recognizing existing peer-reviewed, evidence-based guidelines as a basis for establishing clinical validity of a PGx test. The Association cited FDA data showing that the cost of drug-related morbidity and mortality exceeds $136 billion annually.

“FDA’s actions have the practical effect of taking away valuable tools that physicians rely on for making informed prescribing decisions,” the ACLA asserted. “What FDA is doing will result in more patients getting a less effective or the wrong medication, with negative consequences for patient care and health care costs.

“Additionally, by implementing an effective ban, FDA will chill investment and innovation in the PGx space,” the ACLA added.

An ACLA spokesperson told Clinical OMICs that the FDA has responded to its letter. “Our plan is to have a meeting with the agency in the next few weeks. We hope this is the start of a constructive dialogue on how to address the issues that we have raised in our letter and that continue to have significant consequences for patients,” the spokesperson noted.

The FDA enforcement stance has also drawn concern from the National Alliance on Mental Illness, the National Council for Behavioral Health, the Depression and Bipolar Support Alliance, and Mental Health America. “Although we appreciate the FDA’s mission to protect the public health, in this case we believe the Agency’s actions may in fact inflict greater harm on patients and impede innovation,” the groups stated September 25 in a joint letter to Sharpless and Health and Human Services Secretary Alex M. Azar II.

270 drugs listed

According to Klein, there are currently 270 drugs which the FDA notes as having pharmacogenomic information in the drug label and thus are on the agency’s biomarker list. While the labeling for some therapeutic products includes specific actions to be taken based on the biomarker information, other labels do not have information that can be used by a clinician to change their prescribing behavior.

“Like many other pharmacogenomics organizations, we’re keen to work with the FDA on this issue. We have been in conversations with the FDA and are working to have PharmGKB recognized as an FDA approved resource in the same way that ClinGen is now,” Klein added. “This process will take some time, but we hope that FDA approval will allow knowledge and resources from PharmGKB to augment the work of the FDA and help PharmGKB to reach an even wider audience.”

 

This article was originally published in the November/December 2019 issue of Clinical OMICs. For more content like this and details on how to get a free subscription, go to www.clinicalomics.com.

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