Science Behind Approved OUD Risk Test Questioned

About a year ago, the US Food and Drug Administration (FDA) granted premarket approval to AvertD (SOLVD Health), the first genetic test to assess an individual’s risk of developing opioid use disorder (OUD).

Clinicians and researchers widely denounced the decision and have since called on the FDA to rescind its approval.

Now, new research published earlier this month questions the usefulness of the test, although a spokesman for the company said the study is flawed.

What Led to FDA Approval?

AvertD is a prescription-only test intended to help identify elevated risk of developing OUD in adults being considered for an opioid prescription for acute pain treatment for periods ranging from 4 to 30 days, such as those scheduled for surgical procedures.

A DNA sample obtained through a cheek swab is meant to help guide decisions about opioid prescriptions for patients not previously treated with these drugs, such as an individual undergoing a planned surgery. The proprietary test algorithm considers 15 genetic variants to predict OUD risk.

This information is intended to be used as part of a complete clinical evaluation and risk assessment — not as a standalone to make decisions about prescribing opioids, the FDA said.

In granting AvertD premarket approval (PMA), the FDA acknowledged that there “generally exists some uncertainty around the benefits and risks.”

However, the agency said that “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 OUD, 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.”

In its summary of the data supporting the PMA, the FDA noted that the AvertD test correctly identified an elevated risk for OUD in about 82.8% of cases, equating to a false-negative rate of 18.2% of patients. The false positive rate was 20.8%. The company published similar study results in 2021.

What the New Research Showed

The new study, which was published online January 9 in JAMA Network Open, questions the ability of the genetic test to predict risk for OUD.

In the case-control study of 452,664 adults with lifetime exposure to opioids, the 15 genetic variants collectively accounted for 0.40% of the variation in OUD risk. In comparison, age and sex alone accounted for 3.27% of the variation.

In an independent sample, a machine learning model made up of the 15 genetic variants correctly identified case and control status 52.83% of the time. 

“Only one of the 15 genetic variants used in the proprietary algorithm approved by the FDA to identify individuals at high risk for OUD does so. By itself, that one gene, for which there is good support, is of very limited utility,” study investigator Henry Kranzler, MD, professor of psychiatry and director, Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine in Philadelphia, told Medscape Medical News.

The results “make clear that the FDA made a serious mistake” when it approved the test. “The test can’t predict the risk of OUD any better than a coin flip,” Andrew Kolodny, MD, medical director, Opioid Policy Research Collaborative, Brandeis University, Waltham, Massachusetts, who wasn’t involved in the study, told Medscape Medical News.

Kolodny was one of more than a dozen others who signed a letter sent to the FDA charging that the algorithm used in creating AvertD “fell into known pitfalls of genetic prediction that give the appearance of predicting genetic risk, without being a true measure of genetic risk.”

An invalid genetic test for risk for OUD “is not benign,” Kolodny told Medscape Medical News.

“Patients that test negative, and their prescribers, will be left with a false sense of security, which could lead to overuse, which would make the opioid crisis worse. Patients that test positive may be afraid to take opioids, even in situations when they are beneficial,” he noted.

Company ‘Confident’ in Test Validity

Ron McCullough, PhD, MBA, senior vice-president of clinical operations at SOLVD Health, told Medscape Medical News the company is “confident in the clinical validity and rigor” of AvertD to help “empower informed prescribing decisions for acute pain.”

The researchers in the recent JAMA Network Open publication “did not have access to our technology (AvertD); therefore, any comparisons or conclusions in the article to AvertD are invalid,” McCullough added. 

He also noted that the research relied on “nonvalidated data, biased study populations, and methods inconsistent with established research and clinical standards, limiting its applicability. These limitations undermine their study’s conclusions, which contrast sharply with the robust validation and regulatory review behind AvertD.”

McCullough said AvertD is not meant as a stand-alone tool. “It’s intended to be used with other risk assessment modalities. It’s not a magic bullet, because opioid addiction is complex.”

McCullough said the FDA-mandated post-approval study assessing performance of the test in patients is ongoing.

Medscape Medical News reached out to the FDA for comment on AvertD and received the following response: “HHS [Health and Human Services] has issued a pause on mass communications and public appearances that are not directly related to emergencies or critical to preserving health. This is a short pause to allow the new team to set up a process for review and prioritization. There are exceptions for announcements that HHS divisions believe are mission critical, but they will be made on a case-by-case basis.”

The study by Kranzler and colleagues was supported by awards from the Department of Veterans Affairs; the VISN 4 Mental Illness Research, Education, and Clinical Center; the National Institute on Alcohol Abuse and Alcoholism; and the National Institute on Drug Abuse. Kranzler reported receiving personal fees from Altimmune, Clearmind Medicine, Dicerna Pharmaceuticals, Entheon Biomedical Corp, Eli Lilly and Company, Sophrosyne Pharmaceuticals, Sobrera Pharma, and the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative and grant funding from Alkermes outside the submitted work. Kolodny has served as an expert witness on behalf of states in opioid litigation.