1. ADHD drugs and CV outcomes: Preliminary feasibility study results David J. Graham, MD, MPH on behalf of the FDA Epidemiology Contracts Study Team DSARM Advisory Committee Meeting February 9, 2006

2. FDA’s Epidemiology Contracts Program Replaces Cooperative Agreement Program Provides capability to study safety questions in a population setting and to collaborate with non-govt experts 4 awardees Covered lives HMO Research Network 3.2 million Ingenix (i3 Drug Safety) 12 million Kaiser Permanente Research Institute 6.1 million TN and WA Medicaid 2.2 million Turnover: 1 yr: 8%-30%; 5 yrs: 25%-80% Funding 2005-06$1.6 million 2006-07$0.9 million

3. Feasibility study design Inception cohorts, all ages Study period Jan 1998-June 2005 (i3, KPRI, Medicaid) July 2000-June 2005 (HMO RN) Drugs of interest Amphetamine or dextroamphetamine Methylphenidate Atomoxetine Age-groups Children/adolescents (1-19 years) Adults (20-64 years) Outcomes of interest Sudden unexplained death Acute myocardial infarction Other ischemic heart disease Cerebrovascular accident Arrhythmia Hypertension Pulmonary hypertension

4. Base population characteristics over study period

5. Number of patients treated with ADHD drugs by age-group

6. Person-years (crude) of ADHD drug use by age-group

7. ADHD drug use (% males) by age-group

8. Persistency of ADHD drug use by drug in 0-19 year olds Methylphenidate  Amphetamine  Atomoxetine 

9. Persistency of ADHD drug use by drug in 20+ year olds Methylphenidate  Amphetamine  Atomoxetine 

10. Cardiovascular outcomes of interest: Estimated population background rates Sudden unexplained death Children/adolescents: 1-9 per 10 5 pyrs Adults: Age 20-64: 45 per 10 5 pyrs Age 65+: 700 per 10 5 pyrs Acute myocardial infarction Children/adolescents: 10-20 per 10 5 pyrs Adults: Age 20-64: 200 per 10 5 pyrs Age 65+: 1700 per 10 5 pyrs Stroke (all types) Children/adolescents: 3 per 10 5 pyrs Adults: Age 20-64: 150 per 10 5 pyrs Age 65+: 1200 per 10 5 pyrs Sources: Heart disease and stroke statistics- 2004 update. American Heart Association; US census data, 2000

11. Counts of potential study outcomes within inception cohorts, based on 1  hospital discharge diagnoses AMI: acute myocardial infarction IHD: ischemic heart diseas CVA: cerebrovascular accident (stroke) HTN: hypertension

12. All cause mortality reported within inception cohorts Deaths occurred at any time after cohort entry From any cause In-hospital only from 2 sites, not reported from 1 site Sudden out of hospital deaths included from 1 site 2 sites have death certificate linkage; SCD validated at 1 NDI search required with other 2 sites - turnover, time, $$ Total deaths substantially underestimated

13. Crude frequency of diagnoses that could increase the risk of cardiovascular outcomes in ADHD drug treated patients

14. Power to identify a given risk ratio with a background rate = 15 per 10 5 person-years (AMI in children 1-19 years) Power (1-beta) Exposure cohort person-years (thousands ) 40 80120160200240280320 360400 0.00 0.20 0.40 0.60 0.80 1.00 RR=2 RR=3 RR=5

15. Power to identify a given risk ratio with a background rate = 3 per 10 5 person-years (CVA in children 1-19 years) Power (1-beta) Exposure cohort person-years (thousands) 4080120160200240280320360400 0.00 0.20 0.40 0.60 0.80 1.00 RR=2 RR=3 RR=5 RR=10

16. Power (1-beta) Exposed cohort person-years (thousands) 020406080100 0.00 0.20 0.40 0.60 0.80 1.00 Power to identify a given risk ratio with a background rate = 200 per 10 5 person-years (AMI and CVA in adults 20-64 years) RR=1.5 RR=2 RR=3

17. Probability of excluding a given risk ratio, assuming true RR=1: background = 15 per 10 5 person-years (AMI in children age 1-19) RR=2  RR=3  RR=5 ▲

18. Probability of excluding a given risk ratio, assuming true RR=1: background = 3 per 10 5 person-years (CVA in children age 1-19) RR=2  RR=3  RR=5 ▲ RR=10 ●

19. Probability of excluding a given risk ratio, assuming true RR=1: background = 200 per 10 5 person-years (AMI or CVA in adults age 20-64) RR=2  RR=3 

20. Estimated risk ratio that might be detected with  80% probability by age- and drug-group AMI: acute myocardial infarction CVA: cerebrovascular accident (stroke)

21. Some additional power considerations AMI: acute myocardial infarction CVA: cerebrovascular accident (stroke)

22. Caveats Preliminary results Crude definitions of exposure, outcome Hospital D/C diagnoses, not validated Outcome post 1st Rx; relation to current use not known Out of hospital deaths (SCD) captured at only 1 site Comorbidities broadly defined Could shift with refinement during in-depth study Relationship to outcomes with respect to age not known Power calculations crude Some uncertainty regarding background rates

23. Summary Potential for CV risk with ADHD drugs High prevalence of use in children; growing in adults Sudden unexplained death of 1  interest; most difficult to study TN Medicaid and KPRI have death certificate linkage TN data can go back ~20 years; KPRI ~8 years Other sites would require NDI search Other CV outcomes Feasibility study Exposed person-time substantial for most ADHD drugs CV outcomes require validation; timing with respect to exposure Power probably sufficient to address several outcomes Number of arrhythmia cases seems surprisingly high

24. FDA Epidemiology Contracts ADHD Study Team (listed by site) FDA, ODS Kate Gelperin, MD, MPH Andrew Mosholder, MD, MPH David J. Graham, MD, MPH Judy A. Staffa, PhD HMO Research Network Susan E. Andrade, PhD Ingenix (i3 Drug Safety) K. Arnold Chan, MD, ScD Kaiser Permanente Research Institute Joe Selby, MD, MPH Medicaid (TN and WA) William Cooper, MD, MPH