Title: MPH Label: An opportunity
1MPH 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
2Challenges of interpretation
- Spontaneous reports for AERS weaknesses
- Under-reporting
- Duplicate reports
- Clinicians dont use standardized elicitation
- Clinicians dont use standard coding
- Trials designed for efficacy underpowered to
determine safety - Cant tell how strong or how specific a signal is
3Comorbidity Can Affect Side Effects
- Rate of comorbidity high in ADHD 75
- Dont 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?
4Comorbidity in the MTA Sample (N 579)
ADHD alone
ODD
179 (31)
126 (21)
15
Tic
14
12
8
AnxietyODD
5
4
67 (12)
2
1
11
3
Mood
Conduct
5
43 (7)
26
Anxiety
58 (10)
5Need 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
7Questions 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
8Good 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
9Parents MPH Side Effects ( Patients)
40
35
30
Placebo
25
5mg
10mg
20
15/20 mg
15
10
5
0
Crabby
Appetite
Dull
Insomnia
10Teachers MPH Side Effects (Patients)
30
25
Placebo
20
5mg
10mg
15
15/20 mg
10
5
0
Crabby
Appetite
Dull
Worried
11FDA 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
12MTA Study Growth Rates per Year
13Mean Weight (kg) Across Time (month)
14Weight Gain (2.4 3.0 kg/yr) Vs. Mean Dose
(31.2 12.0 mg), r-0.3d
Dplt0.0001, n212
15FDA 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
16Adverse Events for lead-in titration
- A total of 16/183 (8.7) patients dropped from
the study (n14) or could not tolerate proposed
dosing (n2) due to AEs associated with study
drug for both lead-in titration phases
Note Most patients reported multiple AEs
17Adverse Events in Titration Trial (1)
18Adverse Events in Titration Trial (2)
19Growth tiles ? over 540 days on MPH (n95)
- Significant effect
- for time for both
- weight and BMI
- tiles, Plt0.001
20Preschoolers Need Lower MPH Doses
PK studies comparing Preschoolers and School-Aged
Subjects
Wigal et. al., 2004
21Conclusions
- 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