1. MPH Label: An opportunity Good that FDA is considering a clarification of the MPH label for safety US should invest more in safety monitoring Problems of evaluating a signal from spontaneous reports Need a denominator Studies that should be encouraged

2. Challenges of interpretation Spontaneous reports for AERS weaknesses –Under-reporting –Duplicate reports –Clinicians don’t use standardized elicitation –Clinicians don’t use standard coding –Trials designed for efficacy underpowered to determine safety –Can’t tell how strong or how specific a signal is

3. Comorbidity Can Affect Side Effects Rate of comorbidity high in ADHD: 75% Don’t know if AE is an effect of medication or a symptom of the other disorder Important for parents and clinicians to be aware that treatment with stimulants may impact on comorbidity: put in label?

4. 126 (21%) ODD ADHD alone 179 (31%) Tic 15 Conduct 14 43 (7%) 5 26 12 Anxiety 58 (10%) 11 3 2 1 8 5 4 67 (12%) Mood Comorbidity in the MTA Sample (N = 579)Anxiety+ODD

5. Need to know denominator Adverse events risks should be based on prevalence not only the severity of the risk Evidence based medicine requires Number Need to Treat (NNT) and the Number needed to Harm (NNH) to evaluate the balance of benefit to risk

6. Swanson et al. for the MTA Cooperative Group

7. Questions about the MTA from a Clinician (engaged in “treatment as usual”) “What percentage of the next 100 ADHD patients will improve if I switch from treatment as usual to the MTA medication algorithm?” – increase from 25% (CC) to over 55.6% (MedMgt) “How many additional patients will respond if I then add intensive behavioral treatment? – Increase from 55.6% (MedMgt) to 67.6% (Comb) “If the MTA medication algorithm is not an option, will behavioral treatment alone improve my success rate?” – variable, depending on local conditions Swanson et al. for the MTA Cooperative Group

8. Good that FDA is examining challenge / dechallenge MTA titration trial looked for a dose response in side effects to attribute a problem to the medidation MTA found that parents more sensitive than teachers in seeing the D/R or dose proportionality of MPH

9. Parents: MPH Side Effects (% Patients) 0 5 10 15 20 25 30 35 40 CrabbyAppetiteDullInsomnia Placebo 5mg 10mg 15/20 mg

10. Teachers: MPH Side Effects (%Patients) 0 5 10 15 20 25 30 CrabbyAppetiteDullWorried Placebo 5mg 10mg 15/20 mg

11. FDA clarifying risks a good thing Putting the risks of psychotic reaction in clear language But should also give more information on more common adverse events Growth delay is now more clearly an initial effect of stimulants in preschoolers and schoolage children – should be highlighted

12. MTA Study: Growth Rates per Year

13. Mean Weight (kg) Across Time (month)

14. Weight Gain (2.4 ± 3.0 kg/yr) Vs. Mean Dose (31.2 ± 12.0 mg), r=-0.3 d D p<0.0001, n=212

15. FDA should be encouraged to review entire MPH label The labeling anomaly for MPH –Warning against use of MPH in children under 6 years of age –Approval of d-amphetamine for use down to age 3

16. Adverse Events for lead-in & titration A total of 16/183 (8.7%) patients dropped from the study (n=14) or could not tolerate proposed dosing (n=2) due to AE’s associated with study drug for both lead-in & titration phases Note: Most patients reported multiple AE’s

17. Adverse Events in Titration Trial (1)

18. Adverse Events in Titration Trial (2)

19. Growth %tiles ↓ over 540 days on MPH (n=95) Significant effect for time for both weight and BMI %tiles, P<0.001

20. Preschoolers Need Lower MPH Doses PK studies comparing Preschoolers and School-Aged Subjects Wigal et. al., 2004

21. Conclusions MPH effect sizes were small to moderate (Cohen, 1988) for composite measures of efficacy in preschoolers using best dose mean estimate of 14.1± 8.1 mg (0.75 mg/kg/day) total daily dose Best MPH dose (0.75 mg/kg/day) from controlled PATS titration trial differed from weight adjusted dose (0.96 mg/kg/day) in schoolage children with ADHD reported in MTA Study 8.7% of patients discontinued because of MPH-related AEs that kicked in at 5 mg TID, which differed from schoolage children Growth data over 375 days shows drop in expected growth, gaining 1.5 cm less and 2.5 kg less than expected on MPH MPH effect sizes were small to moderate (Cohen, 1988) for composite measures of efficacy in preschoolers using best dose mean estimate of 14.1± 8.1 mg (0.75 mg/kg/day) total daily dose Best MPH dose (0.75 mg/kg/day) from controlled PATS titration trial differed from weight adjusted dose (0.96 mg/kg/day) in schoolage children with ADHD reported in MTA Study 8.7% of patients discontinued because of MPH-related AEs that kicked in at 5 mg TID, which differed from schoolage children Growth data over 375 days shows drop in expected growth, gaining 1.5 cm less and 2.5 kg less than expected on MPH