Over the years, we have blogged many times on FDA’s approach towards laboratory-developed tests (LDTs) (see, e.g., prior posts here, here, here, here, and here). On October 31, 2018, FDA issued a Safety Communication relating to one particular type of LDT: pharmacogenomic (PGx) assays. On November 1, 2018, the Center for Devices and Radiological Health and the Center for Drug Evaluation and Research issued a joint statement on the same topic.
Pharmacogenomics, or PGx, generally refers to testing and research related to the impact of genetic variants on drug response. A growing body of evidence is emerging to support an association between certain genetic variants and patient response to medication. Scientists and clinicians have been working to review and curate these data and rank the strength of the evidence for specific drugs and variants. By knowing this information, physicians may be able to make more informed prescribing and dosing decisions
FDA has itself acknowledged that pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. See FDA, Table of Pharmacogenomic Biomarkers in Drug Labeling. According to FDA, there are currently 385 known gene-drug interactions in FDA-approved prescribing information for hundreds of drugs; some but not all of these products include specific actions to be taken based on the biomarker information.
In the first quarter of 2019, FDA followed up on its Safety Communication by privately contacting various clinical laboratories and software companies that provide support services to laboratories asking them to cease including information about specific medications in laboratory reports for PGx tests. During this same time period, FDA issued a Warning Letter to Inova Health Systems on April 4, 2019 after that entity refused to comply with FDA’s request.
Subsequently, FDA has continued its campaign of privately contacting companies and insisting that they stop providing physicians with any gene-drug association data (even if the data are included in the FDA-approved drug labeling. For example, Tegretol (carbamazepine) has a black box warning about “serious and sometimes fatal” dermatologic reactions in patients with the HLA-B*15:02 allele. However, complying with FDA’s recent directives would mean that a laboratory that detects the HLA-B*15:02 allele could not include in the test report information alerting the physician of the risk of a serious adverse reaction to Tegretol.
Thus, although FDA did not tell labs to stop performing PGx testing, the agency sought to prohibit labs from providing physicians any information about the potential clinical significance of test results. In effect, FDA said it was up to doctors to sift through the FDA website, guidelines (there are numerous references to PGx data in treatment guidelines), articles, and other sources to try to figure out what the genetic information meant for patients. Although FDA has asserted in the Safety Communication and elsewhere that providing PGx data to physicians poses risks to patients, the agency has not presented any supporting evidence for this assertion.
FDA’s actions here also have implications for the broader debate over regulations of LDTs. FDA has historically said that it would exercise enforcement discretion over LDTs. The agency’s attack on a broad category of LDTs – PGx – without notice or the opportunity for public discussion, and in the absence of a demonstrated risk to the public, is inconsistent with FDA’s long-standing policy of enforcement discretion for LDTs.
On January 9, 2020, Hyman, Phelps & McNamara, P.C. Directors Jeffrey N. Gibbs and Gail H. Javitt filed a citizen petition on behalf of the Coalition to Preserve Access to Pharmacogenomic (PGx) Information. The Coalition is a group of stakeholders, including laboratories, companies that provide support to laboratories, and clinicians who utilize PGx information, committed to providing accurate PGx information to health care providers.
The citizen petition asserts that FDA’s actions violate the Administrative Procedure Act (APA) (both in relation to LDTs generally and PGx tests specifically) and are contrary to the First Amendment. While FDA has repeatedly said that providing PGx information presents safety risks, the agency has provided neither corroboration nor details. On the other hand, it is indisputable that FDA’s actions block the flow of information that can prevent harm and protect patient safety. PGx information can help doctors avoid multiple risks, such as decreased or elevated serum levels, QT prolongation, weight gain, and undesired metabolic changes. PGx information is especially important in the psychiatric field, where, according to the National Alliance on Mental Illness, prescribing that has been informed by PGx information has been shown to result in faster remission for conditions such as Major Depressive Disorder.
The citizen petition asks FDA to:
- Issue a revised Safety Communication clarifying that clinical laboratories and software providers may communicate information about gene-drug interactions that is supported by adequate evidence and is not contraindicated by information in FDA-approved prescribing information.
- Permit clinical laboratories to include medication-specific information in PGx test reports that is included in FDA-approved prescribing information or otherwise supported by adequate evidence without clearance or approval of a premarket submission.
- Conduct any future policy development related to PGx tests in compliance with the APA, which allows for the participation of stakeholders through notice-and-comment rulemaking.
The citizen petition also requests a public hearing before the Commissioner pursuant to 21 C.F.R. Part 15.
All interested stakeholders can comment on the petition through the public docket on Regulations.gov (FDA-2020-P-0152).