The Food and Drug Administration will examine results from a Russian single pivotal efficacy trial of naltrexone to establish whether the drug’s use can be extended to patients with opioid dependence.
Initially approved by the FDA in 2006 for alcohol dependence, the proposed new indication will be reviewed by the agency’s Psychopharmacologic Drugs Advisory Committee on Sept. 16.
Data from a company-sponsored intent-to-treat analysis of the 250 patients enrolled in the ALK21-013 study showed that the 126 patients who were treated once monthly with naltrexone had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo. The trial also met secondary end points of retention in treatment and reduction of desire for opioids, as measured on a visual analog scale of craving. Naltrexone is manufactured by Alkermes Inc. under the name Vivitrol.
The FDA agreed that efficacy data from the manufacturer is strong, but according to a briefing statement posted on its Web site, the agency is looking carefully at the questionably low rate of adverse events that may point to a tendency to underreport them in Russia, where the study was conducted.
“We have been advised that cultural norms in Russia may influence the reporting of adverse events,” the agency said.
According to the FDA, it did not have “a data integrity or quality concern” regarding the Russian results, and Alkermes said in its background materials that the agency inspected four of the Russian sites in July and planned to issue a “No Action Indicated” communication, indicating a clean bill of health.
The issue does not come up directly in the draft list of questions the panel will be asked to answer, being subsumed in a general question about whether the results of the pivotal trial, ALK21-013, can “be applied to the U.S. target population.”
As in other cases in which pivotal evidence comes from foreign trials, the FDA wants the advisory committee to weigh in on whether the foreign population enrolled in the study, as well as the foreign standard of care, might skew the results enough to require a “bridging study” before the drug can be approved for a U.S. population.
The additional hurdle is surely one that naltrexone does not need. The drug has a checkered history as an opioid abuse deterrent to begin with, the FDA noted. “The incorporation of naltrexone into the treatment of addiction in clinical practice has been not entirely enthusiastic. A general impression that the efficacy is limited has been bolstered by the publication of several negative studies.”
But because poor compliance limits the drug’s effectiveness, passive-compliance formulations such as implants, transdermals, or depot injections like naltrexone may help, the agency added.
As the advisory committee convenes, one thing Alkermes has in its favor will be the positive efficacy results from ALK21-013, which the FDA endorsed in its background materials: “We agree with Alkermes that the efficacy study provides convincing evidence that Vivitrol prevents relapse to opioid use in recently detoxified opioid-dependent patients.”
Where the company and the agency part ways is over the question of whether those alleged Russian “cultural norms” cast a shadow over the drug’s safety. “Although the expanded safety database did not identify major new safety issues compared to the established safety profile in the alcohol-dependent population, we noted that the rate of adverse event reporting was distinctly lower in the Russian study compared to the completed studies in the U.S. that were considered under the original NDA review,” the FDA said.
By contrast, Alkermes said, “Overall, the most common adverse events reported in the ALK21-013 trial are consistent with the types of events described in the current Vivitrol package insert for alcohol dependence.”
The FDA noted the following in its safety summary:
P There were no deaths in the naltrexone trials, but there were five in the premarketing safety database, including two suicides and one death each from homicide, pancreatic cancer, and coronary atherosclerosis.
P Three patients in ALK21-013 had a serious adverse event: two HIV-infected patients had SAEs of HIV stage 3 and herpesvirus infection/AIDS, and the third patient had adnexitis. There were four SAEs in the placebo-treated patients.
P In the premarketing database, “adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with Vivitrol than in patients treated with placebo (1% vs. 0).”
P Opioid dependence indication-specific adverse events to watch out for include opioid overdose, hepatic effects and more infections of all types. (The first two did not occur in the ALK21-013 trial.)