CDER Develops New Method to Evaluate an Opioid’s Safety Risk

Regulatory NewsRegulatory News | 08 April 2019 |  By 

As fentanyl analogs present a major risk to public health, and as these analogs can evade prosecution, the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has developed a new computational approach to understand these often-unidentified chemicals better and to assist with drug scheduling.

The new approach, called Public Health Assessment via Structural Evaluation (PHASE), can evaluate the similarity of a newly identified drug of abuse to controlled substances and predict its pharmacology at relevant biological targets, according to a new study on PHASE published Monday in Clinical Pharmacology & Therapeutics.

“One challenge presented by the opioid crisis is that many new drugs of abuse lack proper regulatory control and small modifications to a controlled substance may evade prosecution,” CDER authors write. They discuss how fentanyl analogs account for 80% of the emerging synthetic opioids, and the rate of drug overdose deaths involving synthetic opioids has increased by 88% per year from 2013 to 2016.

The study also explains how this new CDER tool is necessary because the Federal Analogue Act was designed to facilitate the prosecution of chemicals that are structurally “substantially similar” to the parent compound controlled in schedules I or II of the Controlled Substances Act (CSA) but, “The definition of structurally ‘substantially similar’ is ambiguous and compounds not ‘intended’ for human consumption are not covered under the Act. Therefore, prosecuting simple modifications to a parent compound has created an undue burden on law enforcement as the degree of similarity and intent must be proven each time a drug is identified.”

PHASE, however, can proactively inform law enforcement and the public with vital information regarding a new substance by quantifying its structural similarity with drugs previously controlled in the CSA, identifying probable biological targets and predicting binding affinity at the identified biological targets.

When a new drug is identified, a rapid determination can be made in an expandable FDA-constructed controlled substance database as to “whether the drug has ever been evaluated, whether it is being used under a different name, and how similar it is to other controlled substances,” they write.

“The multicomponent computational approach coupled with expert review provides a rapid, systematic evaluation of a new drug in the absence of in vitro or in vivo data. The information provided by PHASE has the potential to inform law enforcement agencies with vital information regarding newly emerging illicit opioids,” the study says.

The study further describes and applies each component of the PHASE protocol to para‐fluoroisobutyryl fentanyl (FIBF), a synthetic opioid linked to at least 62 overdose deaths in Maryland alone.

Assessing the Structural and Pharmacological Similarity of Newly Identified Drugs of Abuse to Controlled Substances Using Public Health Assessment via Structural Evaluation


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Tags: FDA, fentanyl, opioids

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