1. 1 ADHD drugs and CV outcomes: Preliminary feasibility results and potential observational studies David J. Graham, MD, MPH on behalf of the FDA Epidemiology Contracts Study Team March 22, 2006

2. 2 FDA’s Epidemiology Contracts Program Replaces Cooperative Agreement Program Provides capability to study safety questions in a population setting 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. 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. 4 Details of ADHD drug exposure cohorts of children ≤ 19 years

5. 5 Persistency of ADHD drug use by drug in 0-19 year olds Methylphenidate  Amphetamine  Atomoxetine 

6. 6 Background rates for cardiovascular events of interest in pediatric population age 1-19

7. 7 Counts of potential study outcomes in children age 1-19 years, based on hospital discharge diagnoses

8. 8 Deaths reported within pediatric ADHD-drug- exposed inception cohorts Deaths occurred at any time after cohort entry From any cause In-hospital only from 2 sites, none 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, $$

9. 9 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

10. 10 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

11. 11 RR=2 RR=3 RR=5 RR=10 Event number and statistical power required to confirm risk ratios from 2 to 10

12. 12 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

13. 13 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=10 RR=5 RR=3 RR=2

14. 14 Estimated risk ratio that can be detected with  80% probability by age- and drug-group

15. 15 Some additional power considerations AMI: acute myocardial infarction CVA: cerebrovascular accident (stroke)

16. 16 Caveats regarding ADHD cohort study Preliminary data; relationship of drug exposures to outcomes not yet studied Crude definitions of exposure, outcome Hospital D/C diagnoses, not validated Outcome post 1st Rx; timing with current use not known Out of hospital deaths (SCD) not captured at 2 sites Power calculations crude Uncertainty regarding background rates (i.e., AMI)

17. 17 Proposal offered at February advisory meeting Observational echocardiographic study Within a large healthcare database: Identify patients treated with ADHD drugs for varying durations of time Select suitable untreated “controls” from same population Perform echocardiography and assess Left ventricular wall thickness Contractility

18. 18 Patient sampling for echocardiographic study Methylphenidate  Amphetamine  Atomoxetine 

19. 19 Summary Concern regarding potential for CV risk of 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 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 Statistical power and uncertainty Number of arrhythmia cases seems surprisingly high Now in process of obtaining cost estimates for in-depth study

20. 20 FDA Epidemiology Contracts ADHD Study Team (list by site) FDA, ODS Andrew Mosholder, MD, MPH Kate Gelperin, MD, MPH Judy A. Staffa, PhD David J. Graham, MD, MPH 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