Accutane-Psychiatric Disorders

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

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

3. Objectives • 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 • 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 • evaluate spontaneous reports for category, quality and content • determine the value of spontaneous reports in explaining proposed relationships • Review Epidemiology - Conduct Epidemiologic Analyses • evaluate relative likelihood of all risk factors identified • derive relevant conclusions

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

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

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

8. ResultsDistribution of Cases By Category Mood disorders 1247 (53.1%) Anxiety disorders 249 (10.6%) Psychotic disorders 120 (5.1%) Cognitive disturbances 174 (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%)

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

10. Methodology For Evaluation of Individual Spontaneous Reports • Review individual case • Assess coded/reported term • Assess data quality • Assess consistency of data, including onset/offset • Above relative to the 7 reasons on prior slide • 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 • Spontaneous reports are of very diminished value when the outcome has a common background rate

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

13. Mood Disorder Results (cont’d) • 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

14. Psychotic Disorder Results • Of 120 psychotic disorder reports: • 20 dechallenge reports • 5 positive dechallenge and rechallenge reports • 3 reports had a diagnosis of psychotic disorder • 100 other reports: • 9 additional reports with diagnosis • 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

15. Suicidal Behavior Reports • 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 • No apparent dose relationship • 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

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

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

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

19. MDD Morbidity During Any Six Month Exposure Period No Change or 80% Abated then35% Recur 152,500Current Disease 30,500 +42,700 2.5 MillionUS IndividualsAged 15-24 Years 84,000 240,000By History Only 35% Recur orNo Change 182,500 25,290 1. 2% incident cases or No change 2,107,000 No Disease ??? t1 ?# of Accutane-Induced Cases t2 Major DSM IV Depressive Disorder(With acne estimates not available)

20. Observed vs Expected All Other New Total Depressive Incidence Incidence Symptoms & MDD* MDD Disorders Observed 102 336 911 (102+234) Expected 25,000 152,000 ~500,000 -1,000,000 *Major Depressive Disorder

21. Dose & Time to Onset of Background Occurrences Dose10 - 120mg Time to Onset: 0 - 180 days

22. Estimated Prevalence of Substance Abuse In Accutane-Treated Cohort (15-24 yrs) • 7.2% (180,000) heavy alcohol users • 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

23. Alternate Risk Factors • 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 • 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 25-34 is 2% (14,000 expected amongst exposed) • Add alcohol and drug abuse covariates (>3,900 expected amongst exposed)

25. Suicidal Behavior

26. 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 Age < 30 Years Age > 30 Years 95% Population 95% Population DSM-III-R Category Odds Confidence Attributable Odds Confidence Attributable By Gender Ratio Interval P Risk Ratio Interval P Risk WOMEN Any mood disorder 21.3 9.4-48.3 < 0.0001 79.2 58.3 26.3-129.4 < 0.0001 80.8 Any substance use 2.7 1.0-7.3 > 0.05 22.4 3.8 1.2-11.5 < 0.03 26.2 disorder Any antisocial disorder 2.3 0.9-6.2 > 0.05 21.5 1.2 0.2-9.1 > 0.05 6.3 Any anxiety disorder 1.5 0.5-4.7 > 0.05 7.0 1.3 0.5-3.3 > 0.05 5.0 Any eating disorder 8.6 0.8-91.7 > 0.05 14.8 1.1 0.5-6.5 > 0.05 1.6 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 Suicidesin Accutane-Exposed Cohort (United States Data and Estimates) Observed Suicide by Gender & Age Male (33) Female (5) Under 25 Over 25 Unk Under 25 Over 25 Unk Total 27 4 2 5 0 0 38 Male (319) Female (79) Under 25 Over 25 Under 25 Over 25 Total 262 57 48 31 398 Expected Suicide by Gender & Age

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

29. ConclusionMood 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. • 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.

30. ConclusionPsychotic 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. • 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.

31. ConclusionSuicidal Behavior • 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.

32. Overall Conclusion • 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