Can a genetic test predict your risk for opioid addiction?

In December, FDA approved a DNA test called AvertD, which helps providers identify patients' risk of developing an opioid addiction. The test is intended to be used by providers before they prescribe a patient with an opioid for the first time, including before they have surgery. It's not meant for patients with a history of opioid use or for those who experience chronic pain.

In the announcement of AvertD's approval, Jeff Shuren, director of FDA's Center for Devices and Radiological Health, noted that "innovative measures" are needed to prevent, diagnose, treat, and assess patients' risk of developing OUD, given the severity of the opioid crisis.

AvertD is a polygenic risk test, meaning it identifies several genetic variants that, when analyzed together, could suggest an elevated risk of certain diseases. The test specifically analyzes 15 genetic markers that could increase a person's risk for OUD.

In a clinical study of AvertD, researchers analyzed data from 385 participants who had previously been prescribed opioids at least one year prior. Each participant had their cheek swabbed and their DNA analyzed before being evaluated for OUD by a clinician.

Comparing the test's predictions to the clinician's diagnoses, AvertD was able to correctly predict participants who would develop an opioid addiction with 82.5% sensitivity and 79.9% specificity. According to the test's developer SOLVD Health, patients identified by AvertD as having an increased genetic risk of OUD are 18 times more likely to develop an addiction after opioid exposure.

Health experts push back against the test

Even before AvertD's approval, health experts expressed skepticism about its merits. For example, an FDA advisory panel of independent experts voted 11-2 to reject the test, arguing that there was not enough evidence to prove its efficacy.

Although FDA typically follows the recommendations of its advisory committees, it's not required to do so. According to the agency, changes made to the test and additional information provided by SOLVD addressed concerns raised by the advisory agency.

FDA also attached several conditions to the test's approval, such as requirements for SOLVD to provide mandatory training for healthcare providers, as well as fact sheets for patients on how to interpret their test results. To better evaluate its real-world performance, SOLVD is also required to conduct a study of how patients and doctors from different racial and ethnic groups use AvertD.

The test also includes a "black box" warning on its label, which cautions patients about its limitations and emphasizes that it shouldn't be the only measure used to evaluate OUD risk. In addition, both FDA and SOLVD have stressed that the test is intended to be used as part of a broader evaluation of patients.

"It appears that FDA determined that additional safeguards than are typical were warranted to reduce the risk to levels that would achieve an acceptable benefit-risk balance," said James Mullally, a diagnostic regulatory consultant at device firm MCRA and former branch chief of FDA's division of chemistry and toxicology devices.

However, even with the additional conditions associated with the test, some health experts remain concerned about its use and potential impact on patients.

In a letter sent to FDA and CMS, 31 scientists argued that 15 genetic markers were not adequate to reliably predict a person's genetic risk of OUD and that the test failed to account for differences in geographic ancestry, which can skew results. According to an independent analysis published in 2021, algorithms that used the 15 genetic markers to predict opioid addiction performed "no better than a coin flip" after accounting for geographic ancestry.

Inaccurate test results could lead to medical discrimination and stigma for patients who test positive and a false sense of security for patients who test negative, the scientists said.

"This test will make the opioid crisis worse," said Andrew Kolodny, medical director of opioid policy research at Brandeis University and one of the letter's authors. "It will contribute to overprescribing, it will contribute to an increased incidence of opioid use disorder. In other words, [there are] more people becoming newly addicted to opioids."

"I think the FDA was under the impression that this isn't a very good test but it's better than nothing," Kolodny added. "That's where they got it wrong. It's not that it's a not-very-good test, it's that it's 100% bogus."

For its part, SOLVD has defended its methods, saying that its approach does adjust for ancestry and that AvertD's algorithm was trained on validated clinical data from 7,000 people. "For every single one of those 7,000 we went through and did orthogonal Sanger sequencing to make sure it's correct," said SOLVD CEO Keri Donaldson.

Jim McKinney, an FDA spokesperson, has reiterated that the agency believes innovative approaches are needed to address the opioid epidemic. "Given the totality of available evidence and the urgent need for medical devices that can make a positive impact on the overdose crisis, and specifically devices that can help assess the risk of developing opioid use disorder, the FDA determined that there is a reasonable assurance of AvertD's safety and effectiveness, taking into consideration available alternatives, patients' perspectives, the public health need and the ability to address uncertainty through the collection of post-market data," he said.

Mullally also said he agrees with FDA's decision to approve the test, even with the concerns raised by skeptics. In general, he believes doctors will heed FDA's warnings about not relying too heavily on the test's results.

"I trust prescribers to make this complex decision in light of all available information for their patients," Mullally said. (Molteni, STAT, 4/4; Lovelace, Jr., NBC News, 4/4)

The genetic testing marketplace is expanding rapidly. With testing becoming more affordable and increasingly available, providers, health plans, and diagnostics companies must reassess their approaches to genetic testing to take advantage of the full value of genetic tests. Find out how leaders can use a value-based approach to identify the most impactful tests and eliminate unnecessary spending.