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SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
AT AN FDA ADVISORY COMMITTEE MEETING
