FDA Watch: Scientists Ask Agency to Rescind Approval for Opioid Management Test

A test designed to determine whether patients who need pain medication are at risk of misusing opioids has created tension in the scientific community less than a year after the U.S. Food and Drug Administration (FDA) approved the assay for commercial use.

The assay, AvertD, was approved by the FDA on December 19, 2023.¹  In April 2024, a group of more than 30 scientists and academics sent a letter to the agency urging it to rescind that approval.

AvertD is a genotyping test designed to detect and analyze 15 genetic polymorphisms in DNA that indicate whether a patient may be at higher risk of developing opioid use disorder (OUD). DNA samples are drawn from patients via buccal swabs. The test is designed to gauge patients’ compatibility with opioid regimens from four to 30 days in length.² According to the FDA, AvertD is not intended to be used by itself to make treatment-related decisions but rather as part of a full clinical assessment.³

The source of tension over the approval of AvertD stems from its performance in a clinical study AvertD’s parent company, SOLVD Health, sent to the FDA to bolster its application. The test results of 385 randomly selected patients from 812 total enrolled participants indicated an 82.76 percent sensitivity and 79.23 percent specificity, which the FDA said was statistically significant and met “the pre-specified performance goals.”^4,5

When the test was formally approved, Jeff Shuren, MD, director of the FDA’s Center for Devices and Radiological Health at the time, said that “AvertD may help patients who are concerned about being treated with an opioid for acute pain make better informed decisions.”³

Experts say test’s approach is flawed

But members of the scientific community said the test’s performance in the SOLVD Health study wasn’t nearly enough to guarantee the test was an accurate predictor of opioid misuse. They also took issue with the overall approach of the test and its selection of 15 genetic polymorphisms.

“This test is based on an approach that has been abandoned by mainstream genetics. The largest well-powered and state-of-the-art genome-wide studies of OUD to date demonstrate that even a full genome’s worth of markers (roughly 6,000,000) is not sufficient to predict OUD in a clinically useful way,” stated the letter to FDA commissioner Robert Califf, MD. It was signed by 31 scientists, including professors from Stanford University, Johns Hopkins University, Duke University, Georgetown University, and the University of Utah, among others.⁶ The same group sent a similar letter to the Centers for Medicare & Medicaid Services (CMS), asking the agency to deny coverage of the test.⁷

Part of the argument from the group of scientists was a 2021 study in the journal Drug and Alcohol Dependence.⁸ That study “found that the algorithm used for AvertD fell into known pitfalls of genetic prediction that give the appearance of predicting genetic risk, without being a true measure of genetic risk,” both letters noted. “With proper controls for ancestry, genetic predictors from the 15 variants used in AvertD did not predict risk of OUD any better than chance.”^6,7

Michael Abrams, a senior researcher with the consumer group Public Citizen and one of the co-signers of the letters, suggested that the FDA may have approved the test in part due to its introduction in 2022 of a regulatory framework to address opioid addiction in the US. Opioid overdoses cause about 81,000 deaths nationwide each year.⁹

“I think the reason it is relevant is because [the FDA is] hard-pressed—as is the field generally—to get a handle on an epidemic that has proceeded and gotten worse during COVID,” Abrams said. “So, they want to look like they’re doing something, and it would be nice if there was a test that could do what the AvertD purports to do, but there isn’t.”

By relying on the test to inform opioid prescribing, Abrams said that clinicians were running the risk of having overconfidence in their decisions, which could lead to more individuals developing opioid use disorder. Or, they could wind up withholding opioids from some patients out of fear they would abuse the prescription, causing them to suffer unnecessary pain.

Letters “reflect a misunderstanding” of test’s purpose and use, CEO says

SOLVD chief executive officer Keri Donaldson, MD, MSCE, notes in a written response to questions that “AvertD does not predict opioid use disorder; rather it informs patients of their personal genetic risk (whether elevated or non elevated)—prior to being prescribed their first prescription of oral opioids for acute, non-emergent pain—excluding patients being treated for chronic pain.”

Donaldson added that “the test has been shown to demonstrate an 18-fold difference in individuals that have an elevated genetic risk vs non elevated, which are critical insights in informing patients and providers of the genetic risks prior to prescribing.”

The FDA placed some fairly onerous conditions on the approval of AvertD. Among them are an ambitious post-market study. Donaldson said it will require studying 4,000 patients over a five-year period who have taken the test, the course of opioid treatment they receive, and the overall outcomes. He added that the cost of the study will likely run into the tens of millions of dollars. Clinicians also have to be trained by SOLVD on how and when to administer the test.

As for the letters to the FDA and CMS, Donaldson stated that they “reflect a misunderstanding of AvertD’s purpose and application.” He also suggested that professional rivalries may have played a role in their authorship.

“Many of the individuals behind the April letter[s] may have conflicts of interest, including ties to competitive technologies and/or research grants that could potentially have funding impacted,” he said.

However, other members of the scientific community have also raised concerns about the test.¹⁰ “Concern about false positives was one of the reasons that the FDA’s own scientific advisors voted 11-2 against approval of AvertD,” the letter to the FDA points out.⁶

And the FDA’s response to the letter? Abrams said the group of scientists has yet to receive one.

References:

1. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230032A.pdf
2. https://avertdtest.com/
3. https://www.fda.gov/medical-devices/medical-devices-news-and-events/fda-approves-first-test-help-identify-elevated-risk-developing-opioid-use-disorder
4. https://www.fda.gov/media/162381/download
5. https://www.fda.gov/media/162584/download
6. https://www.supportprop.org/wp-content/uploads/2024/04/FDA-AvertD-Letter-4.4.24.pdf
7. https://www.supportprop.org/wp-content/uploads/2024/04/CMS-AvertD-Letter-4.4.24.pdf
8. https://www.sciencedirect.com/science/article/abs/pii/S0376871621006104?via%3Dihub
9. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/202205.htm
10. https://www.fda.gov/media/175344/download

***************

Key recent FDA approvals of laboratory-related platforms, in vitro diagnostic (IVD) devices, and over-the-counter (OTC) tests and products include: