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ZIMULTIZIMULTI
SANOFI-AVENTISSANOFI-AVENTIS
NDA 21-888NDA 21-888
ZIMULTIZIMULTI
SANOFI-AVENTISSANOFI-AVENTIS
NDA 21-888NDA 21-888
Endocrinologic and Metabolic Drugs Advisory Endocrinologic and Metabolic Drugs Advisory Committee MeetingCommittee MeetingSilver Spring, MarylandSilver Spring, MarylandJune 13, 2007June 13, 2007
Amy G. Egan, M.D., M.P.H. Amy G. Egan, M.D., M.P.H. Division of Metabolism and Endocrine ProductsDivision of Metabolism and Endocrine Products
Endocrinologic and Metabolic Drugs Advisory Endocrinologic and Metabolic Drugs Advisory Committee MeetingCommittee MeetingSilver Spring, MarylandSilver Spring, MarylandJune 13, 2007June 13, 2007
Amy G. Egan, M.D., M.P.H. Amy G. Egan, M.D., M.P.H. Division of Metabolism and Endocrine ProductsDivision of Metabolism and Endocrine Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
OutlineOutline
• Efficacy findings and conclusions for the indication of weight management
• Safety concerns– Neurological adverse events– Seizures– Psychiatric adverse events– Suicidality
• Efficacy findings and conclusions for the indication of weight management
• Safety concerns– Neurological adverse events– Seizures– Psychiatric adverse events– Suicidality
3Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
FDA Guidance Criteria for Efficacy FDA Guidance Criteria for Efficacy of Weight-Management Drugsof Weight-Management Drugs
FDA Guidance Criteria for Efficacy FDA Guidance Criteria for Efficacy of Weight-Management Drugsof Weight-Management Drugs
1. The drug’s effect is significantly greater than that of placebo with the mean drug-associated weight loss exceeding mean placebo weight loss by at least 5%.
2. The proportion of subjects who reach and maintain a loss of at least 5% of their initial body weight is significantly greater in subjects on drug than in those on placebo.
1. The drug’s effect is significantly greater than that of placebo with the mean drug-associated weight loss exceeding mean placebo weight loss by at least 5%.
2. The proportion of subjects who reach and maintain a loss of at least 5% of their initial body weight is significantly greater in subjects on drug than in those on placebo.
4Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Efficacy ConclusionsEfficacy ConclusionsEfficacy ConclusionsEfficacy Conclusions
• Rimonabant 20 mg daily along with a hypocaloric diet was shown to reduce body weight by approximately 5% relative to hypocaloric diet plus placebo
• Rimonabant-associated weight loss was accompanied by improvement in levels of triglycerides, HDL-C, and HbA1c in subjects with type 2 DM
• Rimonabant 20 mg daily along with a hypocaloric diet was shown to reduce body weight by approximately 5% relative to hypocaloric diet plus placebo
• Rimonabant-associated weight loss was accompanied by improvement in levels of triglycerides, HDL-C, and HbA1c in subjects with type 2 DM
5Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Efficacy Conclusions (cont’d)Efficacy Conclusions (cont’d)Efficacy Conclusions (cont’d)Efficacy Conclusions (cont’d)
• Relative to placebo, rimonabant had no effect on levels of total cholesterol or LDL-C
• For unclear reasons, reductions in systolic and diastolic blood pressure were less than expected given the degree of weight loss
• Relative to placebo, rimonabant had no effect on levels of total cholesterol or LDL-C
• For unclear reasons, reductions in systolic and diastolic blood pressure were less than expected given the degree of weight loss
6Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
CaveatsCaveatsCaveatsCaveats• High attrition
– Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in this study as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
• High attrition – Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in this study as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
7Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
CaveatsCaveatsCaveatsCaveats• High attrition
– Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in these studies as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
• High attrition – Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in these studies as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
8Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
CaveatsCaveatsCaveatsCaveats• High attrition
– Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in this study as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
• High attrition – Year 1 drop out rates: ~ 32% to 49%– Year 2 drop out rates: ~ 23% to 58%– No systematic follow-up of dropouts
• Last observation carried forward (LOCF) was used in this study as the 1° analytic method
• Generalizability– Middle-aged Caucasian females– Greater efficacy in Caucasian vs. African-
American and younger vs. older– Subjects with a history of significant depression
excluded
9Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant DatabaseRimonabant DatabaseRimonabant DatabaseRimonabant DatabaseAs of 18 December 2006, the cumulative
database for rimonabant consists of:
• 1308 healthy subjects from 37 completed Phase 1 studies
• 1230 patients from 5 completed Phase 2 studies• 13,644 patients from 13 completed Phase 3 studies
– 6761 obese patients in 8 weight management/ diabetes studies
– 6883 patients in 5 smoking cessation studies)
As of 18 December 2006, the cumulative database for rimonabant consists of:
• 1308 healthy subjects from 37 completed Phase 1 studies
• 1230 patients from 5 completed Phase 2 studies• 13,644 patients from 13 completed Phase 3 studies
– 6761 obese patients in 8 weight management/ diabetes studies
– 6883 patients in 5 smoking cessation studies)
10Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Exposure to RimonabantExposure to RimonabantExposure to RimonabantExposure to Rimonabant
• Subject exposure to rimonabant 20 mg indications as of December 18, 2006:– 0 to < 6 months: 2256 subjects – 6 to <12 months: 1619 subjects– 12 to < 18 months: 592 subjects– 18 to 24 months: 441 subjects
• Subject exposure to rimonabant 20 mg indications as of December 18, 2006:– 0 to < 6 months: 2256 subjects – 6 to <12 months: 1619 subjects– 12 to < 18 months: 592 subjects– 18 to 24 months: 441 subjects
11Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Selection of Events of InterestSelection of Events of InterestSelection of Events of InterestSelection of Events of Interest
• Datasets:– Adverse event dataset– Associated psychiatric symptoms
dataset– Controlled substance dataset
• Studies with re-randomization:– Same treatment during the entire
study
• Datasets:– Adverse event dataset– Associated psychiatric symptoms
dataset– Controlled substance dataset
• Studies with re-randomization:– Same treatment during the entire
study
12Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Statistical MethodologyStatistical MethodologyStatistical MethodologyStatistical Methodology
• Meta-analysis stratified by study• Included 14 randomized phase 2 and
3 trials• Per study sample sizes ranged from
20 to 3,000 per group• Study durations ranged from 4 to 104
weeks• Primary treatment comparison:
rimonabant 20 mg vs. placebo
• Meta-analysis stratified by study• Included 14 randomized phase 2 and
3 trials• Per study sample sizes ranged from
20 to 3,000 per group• Study durations ranged from 4 to 104
weeks• Primary treatment comparison:
rimonabant 20 mg vs. placebo
13Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Statistical MethodologyStatistical MethodologyStatistical MethodologyStatistical Methodology
• RR, OR, RD• Safety outcomes with relatively rare events
(seizure, suicidality): an exact meta-analysis and a fixed-effects meta-analysis were used
• Safety outcomes with more common events (neurological AEs and psychiatric AEs): Fixed and random effects meta-analyses were used
• Primary analysis used first randomization data only
• Sensitivity analyses were performed using second randomizations
• RR, OR, RD• Safety outcomes with relatively rare events
(seizure, suicidality): an exact meta-analysis and a fixed-effects meta-analysis were used
• Safety outcomes with more common events (neurological AEs and psychiatric AEs): Fixed and random effects meta-analyses were used
• Primary analysis used first randomization data only
• Sensitivity analyses were performed using second randomizations
14Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Neurological Adverse Neurological Adverse EventsEvents
Neurological Adverse Neurological Adverse EventsEvents
15Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Endocannabinoids and the Endocannabinoids and the Nervous SystemNervous System
Endocannabinoids and the Endocannabinoids and the Nervous SystemNervous System
• CB1 receptors abundant in the cerebellum, cortex, hippocampus, hypothalamus, and basal ganglia (involved in memory, motor function and reward behaviors)
• CB1 receptors also present on the peripheral nerves
• Neuroprotection of CNS and PNS
• CB1 receptors abundant in the cerebellum, cortex, hippocampus, hypothalamus, and basal ganglia (involved in memory, motor function and reward behaviors)
• CB1 receptors also present on the peripheral nerves
• Neuroprotection of CNS and PNS
16Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Neurological Adverse EventsNeurological Adverse EventsNeurological Adverse EventsNeurological Adverse Events
• Occurred in 27.4% of rimonabant 20 mg treated subjects vs. 24.4% of placebo treated subjects
• Responsible for 3.5% of discontinuations in the rimonabant 20 mg treated subjects vs. 1.3% of placebo treated subjects
• Occurred in 27.4% of rimonabant 20 mg treated subjects vs. 24.4% of placebo treated subjects
• Responsible for 3.5% of discontinuations in the rimonabant 20 mg treated subjects vs. 1.3% of placebo treated subjects
17Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Sensory ChangesSensory ChangesSensory ChangesSensory Changes
18Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Motor ImpairmentMotor ImpairmentMotor ImpairmentMotor Impairment
19Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Cognitive DisordersCognitive DisordersCognitive DisordersCognitive Disorders
20Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk for Neurological Relative Risk for Neurological Adverse EventsAdverse Events
RIO StudiesRIO Studies
Relative Risk for Neurological Relative Risk for Neurological Adverse EventsAdverse Events
RIO StudiesRIO Studies
21Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk for Neurological Relative Risk for Neurological Adverse Events Adverse Events Diabetes StudiesDiabetes Studies
Relative Risk for Neurological Relative Risk for Neurological Adverse Events Adverse Events Diabetes StudiesDiabetes Studies
22Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Multiple SclerosisMultiple SclerosisMultiple SclerosisMultiple Sclerosis
• Clinical trials data: Cannabinoids can reduce the spasms, spasticity, or tremor of MS
• Pre-clinical data: Mouse models of MS suggest that CB receptor activation may oppose the progression of MS– Slows neurodegenerative process– Reduces inflammation– Promotes remyelination
• Clinical trials data: Cannabinoids can reduce the spasms, spasticity, or tremor of MS
• Pre-clinical data: Mouse models of MS suggest that CB receptor activation may oppose the progression of MS– Slows neurodegenerative process– Reduces inflammation– Promotes remyelination
23Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Multiple SclerosisMultiple SclerosisMultiple SclerosisMultiple Sclerosis
• Numbers small to date– RIO
• 2 confirmed MS cases on Rim 5 mg• 1 un-confirmed MS case on placebo
– Smoking cessation• 2 suspected cases on Rim 20 mg
– Post-marketing• 1 case of optic neuritis; MRI suggestive of MS• 1 case in subject with MS with exacerbation on Rim
• Lag time to diagnosis• Initial vague symptomatology• Theoretic possibility• Biologically plausible
• Numbers small to date– RIO
• 2 confirmed MS cases on Rim 5 mg• 1 un-confirmed MS case on placebo
– Smoking cessation• 2 suspected cases on Rim 20 mg
– Post-marketing• 1 case of optic neuritis; MRI suggestive of MS• 1 case in subject with MS with exacerbation on Rim
• Lag time to diagnosis• Initial vague symptomatology• Theoretic possibility• Biologically plausible
24Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
SeizuresSeizuresSeizuresSeizures
25Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Endocannabinoids and Seizure Endocannabinoids and Seizure PotentialPotential
Endocannabinoids and Seizure Endocannabinoids and Seizure PotentialPotential
• Endocannabinoid system has been implicated in regulating seizure duration and frequency.
• Seizure activity elicits an increase in endocannabinoids which activate pre-synaptic CB1 receptors with subsequent regulation of neuronal hyperexcitability and seizure termination
• Endocannabinoid system has been implicated in regulating seizure duration and frequency.
• Seizure activity elicits an increase in endocannabinoids which activate pre-synaptic CB1 receptors with subsequent regulation of neuronal hyperexcitability and seizure termination
26Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Pre-Clinical Data Supporting Pre-Clinical Data Supporting Seizure RiskSeizure Risk
Pre-Clinical Data Supporting Pre-Clinical Data Supporting Seizure RiskSeizure Risk
• 6% of rats and mice and 20% of monkeys developed seizures while receiving long-term treatment with doses of rimonabant 0.5-2 times the 20 mg dose versus 1.5% of control mice and no control rats or monkeys
• Rimonabant accumulates 2-fold in the brain with multiple dosing
• 6% of rats and mice and 20% of monkeys developed seizures while receiving long-term treatment with doses of rimonabant 0.5-2 times the 20 mg dose versus 1.5% of control mice and no control rats or monkeys
• Rimonabant accumulates 2-fold in the brain with multiple dosing
27Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Exclusion Criteria Relevant to the Exclusion Criteria Relevant to the Evaluation of SeizureEvaluation of Seizure
Exclusion Criteria Relevant to the Exclusion Criteria Relevant to the Evaluation of SeizureEvaluation of Seizure
• Presence of any clinically significant neurological disease
• Presence of treated epilepsy• Prolonged administration (> 1 week) of
neuroleptics within 3 months prior to screening visit
• Subjects discontinued from the trials if treated with a neuroleptic
• Presence of any clinically significant neurological disease
• Presence of treated epilepsy• Prolonged administration (> 1 week) of
neuroleptics within 3 months prior to screening visit
• Subjects discontinued from the trials if treated with a neuroleptic
28Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Cases of SeizureCases of SeizureCases of SeizureCases of Seizure
29Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk for All Reported Relative Risk for All Reported SeizuresSeizures
Relative Risk for All Reported Relative Risk for All Reported SeizuresSeizures
Rim 20 mg
Rim5 mg
Placebo RR(CI)
All studies 9/3527.3(0.255%)
2/3204.8(0.062%)
5/2811.2(0.178%)
1.43(0.48, 4.72)
Obesity Studies
7/2608(0.268%)
2/2438.7(0.082%)
1/2259.3(0.044%)
6.06(0.94,
137.71)
30Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Seizures in Ongoing StudiesSeizures in Ongoing StudiesSeizures in Ongoing StudiesSeizures in Ongoing Studies
• 8 cases of seizure in ongoing studies– 6 on rimonabant 20 mg– 2 on placebo
• Ongoing studies all have a 1:1 randomization
• 8 cases of seizure in ongoing studies– 6 on rimonabant 20 mg– 2 on placebo
• Ongoing studies all have a 1:1 randomization
31Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Seizure ConclusionsSeizure ConclusionsSeizure ConclusionsSeizure Conclusions
• Biological plausibility linking rimonabant to seizure risk
• Pre-clinical data indicate proconvulsant effect of rimonabant
• Exclusion criteria screened out high-risk individuals from clinical trials
• Although the current clinical data perhaps suggest an increased seizure risk with rimonabant, only clinical experience will clarify this potential risk
• Biological plausibility linking rimonabant to seizure risk
• Pre-clinical data indicate proconvulsant effect of rimonabant
• Exclusion criteria screened out high-risk individuals from clinical trials
• Although the current clinical data perhaps suggest an increased seizure risk with rimonabant, only clinical experience will clarify this potential risk
32Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Psychiatric Adverse Psychiatric Adverse EventsEvents
Psychiatric Adverse Psychiatric Adverse EventsEvents
33Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Endocannabinoids and Psychiatric Endocannabinoids and Psychiatric Disorders Disorders
Endocannabinoids and Psychiatric Endocannabinoids and Psychiatric Disorders Disorders
• Endocannabinoids act as modulators in pathological conditions – Anxiety, phobia, depression, post-traumatic
stress disorder• CB1 receptors are abundant in the pre-frontal
cortex– Regulation of mood, aggression and/or
impulsivity and decision making• CSF levels of the endogenous cannabinoid
anandamide correlate inversely with psychotic symptoms in schizophrenic patients
• Endocannabinoids act as modulators in pathological conditions – Anxiety, phobia, depression, post-traumatic
stress disorder• CB1 receptors are abundant in the pre-frontal
cortex– Regulation of mood, aggression and/or
impulsivity and decision making• CSF levels of the endogenous cannabinoid
anandamide correlate inversely with psychotic symptoms in schizophrenic patients
34Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Exclusion Criteria Relevant to the Exclusion Criteria Relevant to the Evaluation of Psychiatric Adverse Evaluation of Psychiatric Adverse
EventsEvents
Exclusion Criteria Relevant to the Exclusion Criteria Relevant to the Evaluation of Psychiatric Adverse Evaluation of Psychiatric Adverse
EventsEvents• Presence of any clinically significant psychiatric disease
• History of severe depression defined as:– Depression necessitating hospitalization or;– History of 2 or more recurrent episodes of depression or;– History of suicide attempt or;– Prolonged administration (more than 1 week) of anti-
depressants within 3 months prior to screening
• Subjects discontinued from the trials if started on an anti-depressant
• 11,225 subjects were screened for RIO; 113 (1%) failed screening due to these exclusion criteria
• Presence of any clinically significant psychiatric disease
• History of severe depression defined as:– Depression necessitating hospitalization or;– History of 2 or more recurrent episodes of depression or;– History of suicide attempt or;– Prolonged administration (more than 1 week) of anti-
depressants within 3 months prior to screening
• Subjects discontinued from the trials if started on an anti-depressant
• 11,225 subjects were screened for RIO; 113 (1%) failed screening due to these exclusion criteria
35Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Baseline History of Depressed Baseline History of Depressed Mood Disorders and DisturbancesMood Disorders and Disturbances
Baseline History of Depressed Baseline History of Depressed Mood Disorders and DisturbancesMood Disorders and Disturbances
Study Rimonabant20 mg
Rimonabant5 mg
Placebo
Pooled 179/25037%
201/25208%
95/16026%
RIO Europe 33/5995.5%
24/6034.0%
10/3053.3%
RIO Lipids 20/3465.8%
30/3458.7%
12/3423.5%
RIO Diabetes 13/3393.8%
17/3584.7%
24/3486.9%
RIO NorthAmerica
113/12199.3%
130/121410.7%
49/6078.1%
•Ongoing at randomization: 1.4% on rimonabant 20 mg vs. 1.1% on placebo
36Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Psychiatric Adverse Event TermsPsychiatric Adverse Event TermsPsychiatric Adverse Event TermsPsychiatric Adverse Event Terms
• Primary System Organ Class (SOC): Psychiatric Disorders
– High Level Group Terms (HLGT)» Preferred Terms (PT)
– Anxiety Disorders and Symptoms » (anxiety, nervousness, stress, tension)
– Depressed Mood Disorders and Disturbances » (depression, depressed mood, anhedonia,
dysthymic disorder)– Sleep Disorders and Disturbances
» (insomnia, parasomnia, somnolence)– Mood Disorders and Disturbances
» (affect alteration, crying, mood altered)
• Primary System Organ Class (SOC): Psychiatric Disorders
– High Level Group Terms (HLGT)» Preferred Terms (PT)
– Anxiety Disorders and Symptoms » (anxiety, nervousness, stress, tension)
– Depressed Mood Disorders and Disturbances » (depression, depressed mood, anhedonia,
dysthymic disorder)– Sleep Disorders and Disturbances
» (insomnia, parasomnia, somnolence)– Mood Disorders and Disturbances
» (affect alteration, crying, mood altered)
37Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Psychiatric Adverse Event Rates Psychiatric Adverse Event Rates by High Level Group Term (RIO)by High Level Group Term (RIO)
Psychiatric Adverse Event Rates Psychiatric Adverse Event Rates by High Level Group Term (RIO)by High Level Group Term (RIO)
High Level Group Term
Rimonabant 20 mg(N=2176)
N (%)
Placebo(N=1602)
N (%)
Pooled 569 (26) 225 (14)
Anxiety Disorders and Symptoms
233 (11) 79 (5)
Depressed Mood Disorders and Disturbances
196 (9) 83 (5)
Sleep Disorders and Disturbances
170 (8) 67 (4)
Mood Disorders and Disturbances
60 (3) 12 (0.8)
38Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk of Psychiatric AE Relative Risk of Psychiatric AE (RIO)(RIO)
Relative Risk of Psychiatric AE Relative Risk of Psychiatric AE (RIO)(RIO)
39Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk of Psychiatric Relative Risk of Psychiatric Adverse Event by SubgroupsAdverse Event by SubgroupsRelative Risk of Psychiatric Relative Risk of Psychiatric
Adverse Event by SubgroupsAdverse Event by Subgroups
• Age– 65 years or older RR = 3.1– Less than 65 years RR =1.7
• Geographic location– US studies RR = 1.7 – Non-US studies RR = 1.8
• Age– 65 years or older RR = 3.1– Less than 65 years RR =1.7
• Geographic location– US studies RR = 1.7 – Non-US studies RR = 1.8
40Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Relative Risk of Psychiatric Relative Risk of Psychiatric Adverse Event – by Subgroups Adverse Event – by Subgroups
Relative Risk of Psychiatric Relative Risk of Psychiatric Adverse Event – by Subgroups Adverse Event – by Subgroups
• Gender– Males RR = 2.1 – Females RR = 1.7
• 5% Weight-Loss Response– Responders RR = 1.9– Non-responders RR=1.9
• Gender– Males RR = 2.1 – Females RR = 1.7
• 5% Weight-Loss Response– Responders RR = 1.9– Non-responders RR=1.9
41Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Psychiatric Adverse Event by Psychiatric Adverse Event by Baseline History of Depressed Baseline History of Depressed
Mood (RIO)Mood (RIO)
Psychiatric Adverse Event by Psychiatric Adverse Event by Baseline History of Depressed Baseline History of Depressed
Mood (RIO)Mood (RIO)
•1082/1235 (88%) of subjects who experienced a psychiatric adverse event did not have a baseline history of Depressed Mood Disorders and Disturbances
42Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Treatment of Psychiatric Adverse Treatment of Psychiatric Adverse EventsEvents
Treatment of Psychiatric Adverse Treatment of Psychiatric Adverse EventsEvents
Rimonbant 20 mg Placebo
Discontinuation 8.5% 3%
Anxiolytic or hypnotic
8.5% 4.1%
Anti-depressant 4.8% 2.9%
43Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Psychiatric Adverse Events Psychiatric Adverse Events ConclusionsConclusions
Psychiatric Adverse Events Psychiatric Adverse Events ConclusionsConclusions
• Rimonabant 20 mg was associated with an ~ 2-fold increase in the risk of psychiatric adverse events
– Anxiety disorders and symptoms– Depressed mood disorders and
disturbances– Sleep disorders and disturbances
• Rimonabant 20 mg was associated with an ~ 2-fold increase in the risk of psychiatric adverse events
– Anxiety disorders and symptoms– Depressed mood disorders and
disturbances– Sleep disorders and disturbances
44Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
SuicidalitySuicidalitySuicidalitySuicidality
45Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Columbia Suicidality Categories Columbia Suicidality Categories Columbia Suicidality Categories Columbia Suicidality Categories
Category1 Completed suicide2 Suicide attempt 3 Preparatory acts toward imminent
suicide behavior 4 Suicidal ideation 5 Self-injurious behavior, intent
unknown 6 Not enough information (fatal) 9 Not enough information (non-fatal)
Category1 Completed suicide2 Suicide attempt 3 Preparatory acts toward imminent
suicide behavior 4 Suicidal ideation 5 Self-injurious behavior, intent
unknown 6 Not enough information (fatal) 9 Not enough information (non-fatal)
46Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Suicidality AssessmentSuicidality AssessmentSuicidality AssessmentSuicidality Assessment
• 1201 patient narratives assessed by the Posner group
• 91 suicidality cases identified:– Definitely (Columbia categories 1, 2, 3, or 4)– Possibly (Columbia categories 5, 6, or 9)
• Majority of cases were assessed suicidal ideation (Columbia Category 4): – Placebo: 14– Rim 5 mg: 10– Rim 20 mg: 40
• 1201 patient narratives assessed by the Posner group
• 91 suicidality cases identified:– Definitely (Columbia categories 1, 2, 3, or 4)– Possibly (Columbia categories 5, 6, or 9)
• Majority of cases were assessed suicidal ideation (Columbia Category 4): – Placebo: 14– Rim 5 mg: 10– Rim 20 mg: 40
47Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Statistical methodologyStatistical methodologyStatistical methodologyStatistical methodology
• 13 studies used in the analysis• RIO North America and EFC4796 re-
randomized patients– First randomization used in primary
analysis– EFC4796 used the Rim 5 mg group as the
control group (no placebo group in first randomization)
– Sensitivity analyses performed for the 2nd randomization
• 13 studies used in the analysis• RIO North America and EFC4796 re-
randomized patients– First randomization used in primary
analysis– EFC4796 used the Rim 5 mg group as the
control group (no placebo group in first randomization)
– Sensitivity analyses performed for the 2nd randomization
48Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Suicidality Cases in the AnalysesSuicidality Cases in the AnalysesSuicidality Cases in the AnalysesSuicidality Cases in the Analyses
• Total number of suicidality cases contributing to the analyses is 74
• Total number of suicidality cases contributing to the analyses is 74
49Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Odds Ratio of SuicidalityOdds Ratio of SuicidalityAll Studies All Studies
Odds Ratio of SuicidalityOdds Ratio of SuicidalityAll Studies All Studies
50Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Odds Ratio of SuicidalityOdds Ratio of SuicidalityObesity StudiesObesity Studies
Odds Ratio of SuicidalityOdds Ratio of SuicidalityObesity StudiesObesity Studies
51Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Completed SuicidesCompleted SuicidesCompleted SuicidesCompleted Suicides• Four completed suicides reported to date - 3 in entire
rimonabant clinical trial database; 1 post-marketing
• All three in clinical trials have occurred in subjects taking rimonabant:– RIO North America: 63 year-old male on Rim 5 mg– STRADIVARIUS: 36 year-old male on Rim 20 mg– CRESCENDO: 77 year-old male on Rim 20 mg
• Post-marketing: 33 year-old male on Rim 20 mg
• Four completed suicides reported to date - 3 in entire rimonabant clinical trial database; 1 post-marketing
• All three in clinical trials have occurred in subjects taking rimonabant:– RIO North America: 63 year-old male on Rim 5 mg– STRADIVARIUS: 36 year-old male on Rim 20 mg– CRESCENDO: 77 year-old male on Rim 20 mg
• Post-marketing: 33 year-old male on Rim 20 mg
52Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association? • Bias
– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”
• Chance– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”
• Chance– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
53Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Ascertainment BiasAscertainment BiasAscertainment BiasAscertainment Bias
• Patients who report common drug-related adverse events may be questioned more about other adverse events compared with placebo patients– e.g., increased reporting of sexual dysfunction in depressed
patients taking an antidepressant might lead to further questions about other adverse events and possibly increase the odds of reporting suicidal symptoms
• Most common adverse event in rimonabant-treated patients is nausea
• Would increased reporting of nausea in a population of non-depressed patients on rimonabant lead to increased reporting of suicidal symptoms?
– Depressive and anxiety events were reported on average 2 months later than nausea events
• Patients who report common drug-related adverse events may be questioned more about other adverse events compared with placebo patients– e.g., increased reporting of sexual dysfunction in depressed
patients taking an antidepressant might lead to further questions about other adverse events and possibly increase the odds of reporting suicidal symptoms
• Most common adverse event in rimonabant-treated patients is nausea
• Would increased reporting of nausea in a population of non-depressed patients on rimonabant lead to increased reporting of suicidal symptoms?
– Depressive and anxiety events were reported on average 2 months later than nausea events
54Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)
• Increased contact of rimonabant-treated patients with investigators (for any reason) would provide more opportunity to voice suicidal symptoms compared with placebo-treated patients
– The mean and median number of study visits were 11.6 and 15 respectively, for both the placebo and rimonabant groups
– All datasets with unscheduled visits recorded were reviewed – no disproportionately between treatment groups in the number of unscheduled visits
• Increased contact of rimonabant-treated patients with investigators (for any reason) would provide more opportunity to voice suicidal symptoms compared with placebo-treated patients
– The mean and median number of study visits were 11.6 and 15 respectively, for both the placebo and rimonabant groups
– All datasets with unscheduled visits recorded were reviewed – no disproportionately between treatment groups in the number of unscheduled visits
55Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)Ascertainment Bias (cont’d)
• Would have to be operative in 9 of 13 studies and explain odds ratios varying in magnitude from 1.4 to 16.7
• Assumes an equal background rate of depression in placebo and rimonabant-treated subjects
– Recall:• Depressed mood disorders: 9% for rimonabant
subjects vs. 5% for placebo• Discontinuation due to depressive disorders: 4.2%
for rimonabant vs. 1.9% for placebo• Required anti-depressant therapy: 5% for rimonabant
vs. 3% for placebo
• Background rate should obscure differences over time
• Would have to be operative in 9 of 13 studies and explain odds ratios varying in magnitude from 1.4 to 16.7
• Assumes an equal background rate of depression in placebo and rimonabant-treated subjects
– Recall:• Depressed mood disorders: 9% for rimonabant
subjects vs. 5% for placebo• Discontinuation due to depressive disorders: 4.2%
for rimonabant vs. 1.9% for placebo• Required anti-depressant therapy: 5% for rimonabant
vs. 3% for placebo
• Background rate should obscure differences over time
56Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”• Chance
– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”• Chance
– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
57Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Suicidality and Weight ChangeSuicidality and Weight ChangeSuicidality and Weight ChangeSuicidality and Weight Change
RIO suicidality patients (n=28)-20
-16
-12
-8
-4
0
4
8
12
16
20W
t ch
an
ge f
rom
baselin
e (
kg
)
Mean= -4.5 kg (no suicidality patients n=4007)Weight change (Mean=-2.14 kg, suicidality patients)Upper (1 SD)Lower (1 SD)
58Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”
• Chance– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”
• Chance– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
59Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
Rimonabant and SuicidalityRimonabant and SuicidalityWhat is the Nature of the Association?What is the Nature of the Association?
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”• Chance
– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
• Bias– Ascertainment
• Confounding– Weight loss itself
• “Semi-starvation neurosis”• Chance
– Can never exclude the possibility of chance– Replication of findings across 9 of 13 studies
• Causal– Biologically plausible
• ECS and CB1 receptor functions in CNS– Increased incidence of depression in clinical trials– Suicidality is a symptom of depression
60Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Rimonabant and Suicidality Rimonabant and Suicidality SummarySummary
Rimonabant and Suicidality Rimonabant and Suicidality SummarySummary
• Meta-analysis indicates an increased risk for suicidality, specifically suicidal ideation, in subjects taking rimonabant 20 mg vs placebo– ↑ Relative risk ~ 80 to 100%– ↑ Absolute risk ~ 0.3%– NNH ~ 1 in 300 patients
• Estimates may be low given that:– Higher percentage of rimonabant patients
dropped out of studies due to psychiatric adverse events
• Meta-analysis indicates an increased risk for suicidality, specifically suicidal ideation, in subjects taking rimonabant 20 mg vs placebo– ↑ Relative risk ~ 80 to 100%– ↑ Absolute risk ~ 0.3%– NNH ~ 1 in 300 patients
• Estimates may be low given that:– Higher percentage of rimonabant patients
dropped out of studies due to psychiatric adverse events
61Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
European ExperienceEuropean ExperienceEuropean ExperienceEuropean Experience
• Rimonabant approved in 30 countries• As of March 1, 2007, an estimated 100,000 people (mostly from the
UK and Germany) have been prescribed rimonabant• Top 10 Preferred Terms:
– Depression– Nausea– Depressed mood– Anxiety– Fatigue– Dizziness– Sleep disorder– Suicidal ideation– Agitation– Asthenia
• Rimonabant approved in 30 countries• As of March 1, 2007, an estimated 100,000 people (mostly from the
UK and Germany) have been prescribed rimonabant• Top 10 Preferred Terms:
– Depression– Nausea– Depressed mood– Anxiety– Fatigue– Dizziness– Sleep disorder– Suicidal ideation– Agitation– Asthenia
62Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
EMEA PostMarketing DataEMEA PostMarketing Data(Cumulative Since Approval)(Cumulative Since Approval)EMEA PostMarketing DataEMEA PostMarketing Data
(Cumulative Since Approval)(Cumulative Since Approval)
Drug # Psych AE cases
Total AE cases
Psych/Total
Rim (2006)
208 384 54%
Sib (1999)
117 567 21%
Orl (1998)
208 2734 8%
63Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
EMEA PostMarketing DataEMEA PostMarketing Data(Cumulative Since Approval)(Cumulative Since Approval)EMEA PostMarketing DataEMEA PostMarketing Data
(Cumulative Since Approval)(Cumulative Since Approval)
• Cases of suicidal ideation:
– Orlistat (1998) 14 cases
– Sibutramine (1999) 15 cases
– Rimonabant (2006) 27 cases
• Cases of suicidal ideation:
– Orlistat (1998) 14 cases
– Sibutramine (1999) 15 cases
– Rimonabant (2006) 27 cases
64Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Benefit vs. HarmBenefit vs. HarmBenefit vs. HarmBenefit vs. Harm
• Weight loss • TG, HDL• HbA1C• Fasting insulin• Yet to be identified
• Weight loss • TG, HDL• HbA1C• Fasting insulin• Yet to be identified
• Psychiatricsuicidalitydepressionanxiety
• Neurological dizzinessparesthesia/dysesthesiatremorseizure?Nausea/vomiting
• Yet to be identified
• Psychiatricsuicidalitydepressionanxiety
• Neurological dizzinessparesthesia/dysesthesiatremorseizure?Nausea/vomiting
• Yet to be identified
Potential Benefits Potential Harms
65Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
CRESCENDOCRESCENDOCRESCENDOCRESCENDO
• Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes
• 17,000 abdominally obese patients at risk for cardiovascular disease
• Rimonabant 20 mg vs. placebo• ~ 5 years in duration• Primary outcome: myocardial infarction, stroke,
or cardiovascular death• To be completed in 2010
• Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes
• 17,000 abdominally obese patients at risk for cardiovascular disease
• Rimonabant 20 mg vs. placebo• ~ 5 years in duration• Primary outcome: myocardial infarction, stroke,
or cardiovascular death• To be completed in 2010
66Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements
Medical Review Team Pharmacology/ToxicologyEric Colman, M.D. John Gong, Ph.D.Mary Parks, M.D. Karen Davis-Bruno, Ph.D.
Statistical Review Team Lee Ping Pian, Ph.D. J. Todd Sahlroot, Ph.D.
Project Manager Patricia Madara
Medical Review Team Pharmacology/ToxicologyEric Colman, M.D. John Gong, Ph.D.Mary Parks, M.D. Karen Davis-Bruno, Ph.D.
Statistical Review Team Lee Ping Pian, Ph.D. J. Todd Sahlroot, Ph.D.
Project Manager Patricia Madara
67Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Questions for the Advisory Questions for the Advisory CommitteeCommittee
Questions for the Advisory Questions for the Advisory CommitteeCommittee
1. Please discuss your level of concern regarding rimonabant and psychiatric adverse events, in particular depression and suicidality, and neurological adverse events, in particular seizures, and the reasons behind your thinking on these issues.
2a. Do you believe that the currently available data sufficiently characterize rimonabant’s safety profile (vote requested)?
2b. If no, please discuss what additional data should be obtained.
1. Please discuss your level of concern regarding rimonabant and psychiatric adverse events, in particular depression and suicidality, and neurological adverse events, in particular seizures, and the reasons behind your thinking on these issues.
2a. Do you believe that the currently available data sufficiently characterize rimonabant’s safety profile (vote requested)?
2b. If no, please discuss what additional data should be obtained.
68Endocrinologic and Metabolic Drugs Advisory CommitteeEndocrinologic and Metabolic Drugs Advisory CommitteeJune 13, 2007June 13, 2007
Questions for the Advisory Questions for the Advisory CommitteeCommittee
Questions for the Advisory Questions for the Advisory CommitteeCommittee
3a. Based on the currently available data, do you believe rimonabant has a favorable risk-benefit profile and should be approved for the indication of weight management in individuals with a body mass index of > 30 kg/m2 and > 27 kg/m2 when accompanied by at least one comorbid condition (vote requested)?
3b. If no, please explain why and discuss what additional information the sponsor could obtain that might improve rimonabant’s risk-benefit profile.
3a. Based on the currently available data, do you believe rimonabant has a favorable risk-benefit profile and should be approved for the indication of weight management in individuals with a body mass index of > 30 kg/m2 and > 27 kg/m2 when accompanied by at least one comorbid condition (vote requested)?
3b. If no, please explain why and discuss what additional information the sponsor could obtain that might improve rimonabant’s risk-benefit profile.