1. Accutane-Psychiatric Disorders A Pharmacoepidemiological Safety Assessment Robert C. Nelson, PhD RCN Associates, Inc. Annapolis, MD

2. Presentation Overview Objectives Objectives Literature review and model generation Literature review and model generation Spontaneous report reviews Spontaneous report reviews Epidemiology Epidemiology Conclusions Conclusions

3. Objectives To determine the nature and extent of any relationship between Accutane therapy and psychiatric morbidity To determine the nature and extent of any relationship between Accutane therapy and psychiatric morbidity 1)Describe the types of reported psychiatric disorders 2)Identify all associated risk factors 3)Assess the magnitude of the identified risk factors 4)Evaluate causality within the pharmacoepidemiologic framework

4. Methodological Overview Literature Review Literature Review –determine scope of work and related disciplines –comprehensively review and evaluate literature (250 citations) –review etiology and epidemiology of psychiatric conditions (including suicidal behavior) –conceptualize proposed relationships Review Spontaneous Reports Review Spontaneous Reports –evaluate spontaneous reports for category, quality and content –determine the value of spontaneous reports in explaining proposed relationships Review Epidemiology - Conduct Epidemiologic Analyses Review Epidemiology - Conduct Epidemiologic Analyses –evaluate relative likelihood of all risk factors identified –derive relevant conclusions

5. Presentation Overview Objectives Objectives Literature review (Dr. Jacobs) Literature review (Dr. Jacobs) Spontaneous report reviews Spontaneous report reviews Epidemiology Epidemiology Conclusions Conclusions

6. Presentation Overview Objectives Objectives Literature review and model generation Literature review and model generation Spontaneous report reviews Spontaneous report reviews Epidemiology Epidemiology Conclusions Conclusions

7. Spontaneous Report Case Retrieval WHOART SOC. 500 - All Psychiatric Cases by “Reporter Term” WHOART SOC. 500 - All Psychiatric Cases by “Reporter Term” 8 functional diagnostic categories (DSM-IV) 8 functional diagnostic categories (DSM-IV) Reviewed reports received between 1982 and April 30, 1999 Reviewed reports received between 1982 and April 30, 1999 Worldwide Worldwide

8. Mood disorders1247(53.1%) Anxiety disorders 249(10.6%) Psychotic disorders 120(5.1%) Cognitive disturbances174(7.4%) Sleep disorders 82(3.5%) Personality disorders 41(1.7%) Suicidal behavior 168(7.1%) Excluded terms 265(11.3%) Total: 2346(100%) Results Distribution of Cases By Category

9. Reasons For Suspecting A Possible Relationship Between A Drug And An Adverse Event Temporal association Temporal association Dose-response Dose-response Dechallenge Dechallenge Rechallenge Rechallenge Mechanism Mechanism Class Effect Class Effect Absence of alternatives Absence of alternatives

10. Methodology For Evaluation of Individual Spontaneous Reports Review individual case Review individual case Assess coded/reported term Assess coded/reported term Assess data quality Assess data quality Assess consistency of data, including onset/offset Assess consistency of data, including onset/offset Above relative to the 7 reasons on prior slide Above relative to the 7 reasons on prior slide Then, review as case series Then, review as case series

11. Interpretation of Spontaneous Reports When spontaneous reports are well documented and for rare ADRs that have background rates that are low, the spontaneous reports yield the most defensible data When spontaneous reports are well documented and for rare ADRs that have background rates that are low, the spontaneous reports yield the most defensible data Spontaneous reports are of very diminished value when the outcome has a common background rate Spontaneous reports are of very diminished value when the outcome has a common background rate

12. Mood Disorder Results Of 1247 mood disorder reports: Of 1247 mood disorder reports: – 367 dechallenge reports 23 positive dechallenge and rechallenge reports 23 positive dechallenge and rechallenge reports 37 reports had mood disorder diagnosis subsequent to exposure 37 reports had mood disorder diagnosis subsequent to exposure 3 14 1 8 0 8 4 30 Health Professional ConsumerOtherTotal Dechallenge/Rechallenge Reports (34) Mood Symptoms or Disorders Dx No Dx Dx Dx Dx

13. Mood Disorder Results (cont’d) Even the dechallenge reports had a high level of diversity/inconsistency Even the dechallenge reports had a high level of diversity/inconsistency In summary: At the individual case level, a small number of cases imply a causal association between depressive symptoms and/or mood disorders, and Accutane In summary: At the individual case level, a small number of cases imply a causal association between depressive symptoms and/or mood disorders, and Accutane

14. Psychotic Disorder Results Of 120 psychotic disorder reports: Of 120 psychotic disorder reports: – 20 dechallenge reports – 5 positive dechallenge and rechallenge reports 3 reports had a diagnosis of psychotic disorder 3 reports had a diagnosis of psychotic disorder – 100 other reports: 9 additional reports with diagnosis 9 additional reports with diagnosis No pattern of consistency in the available data No pattern of consistency in the available data In summary: At the individual case level, at least 3 reports imply a causal association between the described psychotic disorder and Accutane administration In summary: At the individual case level, at least 3 reports imply a causal association between the described psychotic disorder and Accutane administration

15. Suicidal Behavior Reports Total of 168 reports of suicidal behavior (1982 to April 30, 1999) Total of 168 reports of suicidal behavior (1982 to April 30, 1999) –104 reported suicide attempts –64 reports of completed suicides Overall suicide reports were poorly documented; none had psychological autopsy Overall suicide reports were poorly documented; none had psychological autopsy No apparent dose relationship No apparent dose relationship Ratio of M/F is 5 to 1 for completed suicide reports Ratio of M/F is 5 to 1 for completed suicide reports In summary: None of the 168 reports implies direct causality between suicidal behavior and Accutane administration, at the individual case level In summary: None of the 168 reports implies direct causality between suicidal behavior and Accutane administration, at the individual case level

16. Presentation Overview Objectives Objectives Literature review and model generation Literature review and model generation Spontaneous report reviews Spontaneous report reviews Epidemiology & Epidemiological Analyses Epidemiology & Epidemiological Analyses Conclusions Conclusions

17. Demographics of Accutane Patients Accutane use Accutane use –70% in 15-24 age group 85% of males 85% of males 55% of females 55% of females

18. Prevalence of Major Depressive Disorder (MDD): Age 15-24 30-day: 6.1% (4.3% M::8.2% F) 30-day: 6.1% (4.3% M::8.2% F) 12-month: 10.3% (9.5% M::16.3% F) 12-month: 10.3% (9.5% M::16.3% F) Lifetime: 17.1% (11.0% M::20.8% F) Lifetime: 17.1% (11.0% M::20.8% F)

19. 2.5 Million US Individuals Aged 15-24 Years 182,500 30,500 +42,700 84,000 25,290 ??? Major DSM IV Depressive Disorder ( With acne estimates not available) t1t1 t2t2 152,500 Current Disease 240,000 By History Only 2,107,000 No Disease No Change or 80% Abated then 35% Recur 35% Recur or No Change 1. 2% incident cases or No change ?# of Accutane- Induced Cases MDD Morbidity During Any Six Month Exposure Period

20. Observed vs Expected *Major Depressive Disorder All Other New Total Depressive Incidence Incidence Symptoms & MDD* MDD Disorders Observed102336 911 (102+234) Expected25,000152,000~500,000 -1,000,000

21. Dose 10 - 120mg Time to Onset: 0 - 180 days Dose & Time to Onset of Background Occurrences

22. Estimated Prevalence of Substance Abuse In Accutane-Treated Cohort (15-24 yrs) 7.2% (180,000) heavy alcohol users 7.2% (180,000) heavy alcohol users Approximately same number of illicit drug abusers Approximately same number of illicit drug abusers Assuming extensive co-morbidity, combined alcohol and illicit drug abuse includes approximately 250,000 (10% of exposed) young Accutane patients Assuming extensive co-morbidity, combined alcohol and illicit drug abuse includes approximately 250,000 (10% of exposed) young Accutane patients

23. Alternate Risk Factors Nearly one-quarter million alcohol/substance abusers are amongst the 2.5 million of Accutane-exposed cohort Nearly one-quarter million alcohol/substance abusers are amongst the 2.5 million of Accutane-exposed cohort Many of these abusers are also comorbid with the 152,000 incident mood disorder cases or with people with depressive symptoms or different disease Many of these abusers are also comorbid with the 152,000 incident mood disorder cases or with people with depressive symptoms or different disease The total numbers in the cohort with some form DSM- IV disorder may be up to 16-20% (up to 1/2 million) of the total cohort The total numbers in the cohort with some form DSM- IV disorder may be up to 16-20% (up to 1/2 million) of the total cohort

24. Psychotic Disorders - Alternate Risk Factors Prevalence in ages 15-24 is 1% (25,000 expected amongst exposed) Prevalence in ages 15-24 is 1% (25,000 expected amongst exposed) Prevalence in ages 25-34 is 2% (14,000 expected amongst exposed) Prevalence in ages 25-34 is 2% (14,000 expected amongst exposed) Add alcohol and drug abuse covariates (>3,900 expected amongst exposed) Add alcohol and drug abuse covariates (>3,900 expected amongst exposed)

25. Suicidal Behavior

26. WOMEN Any mood disorder 21.3 9.4-48.3< 0.000179.2 58.3 26.3-129.4< 0.000180.8 Any substance use 2.71.0-7.3> 0.0522.43.81.2-11.5< 0.0326.2 disorder Any antisocial disorder2.30.9-6.2> 0.0521.51.20.2-9.1> 0.056.3 Any anxiety disorder1.50.5-4.7> 0.057.01.30.5-3.3> 0.055.0 Any eating disorder8.60.8-91.7> 0.0514.81.10.5-6.5> 0.051.6 95% Population 95% Population DSM-III-R Category Odds Confidence Attributable Odds Confidence Attributable By Gender Ratio Interval P Risk Ratio Interval P Risk Age < 30 YearsAge > 30 Years Risk of a Serious Suicide Attempt Adjusted for Confounding Mental Disorders, by Gender and Age, for 302 Persons Who Made Serious Suicide Attempts and 1,028 Comparison Subjects SOURCE: Beautrais, A.L, et al. (1996) Prevalence and Comorbidity of Mental Disorders in Persons Making Serious Suicide Attempts: A Case-Control Study. American Journal of Psychiatry, 153(8): 1012

27. Observed vs Expected Suicides in Accutane-Exposed Cohort (United States Data and Estimates) Male (33)Female (5) Under 25Over 25UnkUnder 25Over 25UnkTotal 274250038 Male (319)Female (79) Under 25Over 25Under 25Over 25Total 262574831398 Observed Suicide by Gender & Age Expected Suicide by Gender & Age

28. Presentation Overview Objectives Objectives Literature review and model generation Literature review and model generation Spontaneous report reviews Spontaneous report reviews Epidemiology Epidemiology Conclusions Conclusions

29. Conclusion Mood Disorders There are a small number of reported cases that imply causality between depressive symptoms or mood disorders and Accutane administration, at the individual case level. There are a small number of reported cases that imply causality between depressive symptoms or mood disorders and Accutane administration, at the individual case level. However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more likely to be associated with factors other than Accutane. However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more likely to be associated with factors other than Accutane. Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled out, no matter how unlikely it may appear. Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled out, no matter how unlikely it may appear.

30. Conclusion Psychotic Disorders There are a very small number (3) of reported cases that imply causality between a described psychotic disorder and Accutane administration, at the individual case level. There are a very small number (3) of reported cases that imply causality between a described psychotic disorder and Accutane administration, at the individual case level. However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more likely to be associated with factors other than Accutane. However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more likely to be associated with factors other than Accutane. Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled out, no matter how unlikely it may appear. Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled out, no matter how unlikely it may appear.

31. Conclusion Suicidal Behavior There are no reports amongst the 168 reviewed that imply direct causality between suicidal behavior and Accutane. There are no reports amongst the 168 reviewed that imply direct causality between suicidal behavior and Accutane. An assessment in the context of natural history and alternative risk factors provides strong supporting evidence that the reported cases are much more likely to be due to factors other than Accutane. An assessment in the context of natural history and alternative risk factors provides strong supporting evidence that the reported cases are much more likely to be due to factors other than Accutane.

32. Overall Conclusion Given: Given: –no biological plausibility –no consistent patterns in the data –complex environment of background symptoms –very high background rates of disease –very high background rates of alternative risk factors There is no evidence in these data to support a causal relationship between Accutane administration and psychiatric disorders There is no evidence in these data to support a causal relationship between Accutane administration and psychiatric disorders