Martin Berman-Gorvine

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”

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.)

The FDA has granted naltrexone priority review status, with a target date of Oct. 12 under the Prescription Drug User Fee Act.

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.)

The FDA has granted naltrexone priority review status, with a target date of Oct. 12 under the Prescription Drug User Fee Act.

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.)

The FDA has granted naltrexone priority review status, with a target date of Oct. 12 under the Prescription Drug User Fee Act.