mph label: an opportunity good that fda is considering a clarification of the mph label for safety...
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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
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
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?
126 (21%)126 (21%)
ODDODDADHD aloneADHD alone179 (31%)179 (31%)
TicTic 1515
ConductConduct
1414
43 (7%)43 (7%)55
2626
1212
AnxietyAnxiety58 (10%)58 (10%)
111133
2211
8855
44 67 (12%)67 (12%)
MoodMood
Comorbidity in the MTA Sample (N = 579)
Anxiety+ODDAnxiety+ODD
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
DBD Cumulative Distributions(Parent Teacher Average)
0
10
20
30
40
50
60
70
80
90
100
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3Score
Pe
rce
nt
LNCG
Comb
Med
Beh
CC
Phase B - Comb
Phase B - Med
Phase B - Beh
Phase B - CC
Comb
67.6%
Med
55.6%
Beh
33.8%
CC
25.3%
(Not at All) (Just a Little) (Pretty Much) (Very Much)
LNCG
87.6%
Swanson et al. for the MTA Cooperative Group
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 conditionsSwanson et al. for the MTA Cooperative Group
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
Parents: MPH Side Effects (% Patients)
00
55
1010
1515
2020
2525
3030
3535
4040
CrabbyCrabby AppetiteAppetite DullDull InsomniaInsomnia
PlaceboPlacebo5mg5mg10mg10mg15/20 mg15/20 mg
Teachers: MPH Side Effects (%Patients)
00
55
1010
1515
2020
2525
3030
CrabbyCrabby AppetiteAppetite DullDull WorriedWorried
PlaceboPlacebo5mg5mg10mg10mg15/20 mg15/20 mg
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
MTA Study: Growth Rates per Year
GrowthMeasure
BehavioralTreatment(N=112)
CommunityComparison(N=112)
CombinedTreatment(N=113)
MedicationManagement(N=112)
F p
MeanWeightGain(kg/yr)
4.3 3.4 3.2 2.9 2.8 2.9 1.9 3.1 10.6 0.0001a
MeanHeightGain(cm/yr)
6.3 1.9 5.7 1.4 4.9 1.6 4.8 1.4 21.5 0.0001b
a = Duncan’s Test for Weight: BEH > CC, COMB > MedMgt.b = Duncan’s Test for Height: BEH > CC > COMB, MedMgt.
Mean Weight (kg) Across Time (month)
Time (month)
0 5 10 15 20 25 30
Mea
n W
eig
ht (
kg)
28
30
32
34
36
38
40
42
44
AssessmentCombinedMedicationPsychosocial
Weight Gain (2.4 ± 3.0 kg/yr) Vs. Mean Dose (31.2 ± 12.0 mg), r=-0.3d
Mean Dose (mg)
0 10 20 30 40 50 60 70
We
igh
t Ga
in (
kg/y
r)
-10
-5
0
5
10
15
20
25
CombinedMedicationRegression Line
Dp<0.0001, n=212
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
Adverse Events for lead-in & titrationAdverse 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
• 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’sNote: Most patients reported multiple AE’s
Adverse Event DescriptionCrying/Irritability/Emotional OutburstsInsomniaTicsHeadache/StomachacheDepression/AnxietyAppetite LossHyperactivityVomitingFrequent StoolsTirednessRashesFormicationPossible SeizureSevere Impulsivity/Agitation
11
Reasons for Dropping From Study Due to AE's
Number of Dropped Patients reporting115422
111
1111
Adverse Events in Titration Trial (1)Adverse Events in Titration Trial (1)AE: Emotional Outbursts
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
epo
rted
AE: Stomach or Abdominal Discomfort
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
epo
rted
AE: Irritability
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
ep
ort
ed
Adverse Events in Titration Trial (2)Adverse Events in Titration Trial (2)
AE: Difficulty Falling Asleep
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
ep
ort
ed
AE: Appetite Decrease
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
epo
rte
d
AE: Difficulty Falling Asleep
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
ep
ort
ed
AE: Appetite Decrease
0
2
4
6
8
PL 1.25 mg 2.5 mg 5.0 mg 7.5 mg
Dose
% R
epo
rte
d
Growth %tiles ↓ over 540 days on MPH (n=95)
30
40
50
60
70
80
90
100
Baseline End of Maintenance
%ti
le
Weight
BMI
• Significant effect for time for both weight and BMI %tiles, P<0.001
Preschoolers Need Lower MPH DosesPK studies comparing Preschoolers and School-Aged Subjects
Wigal et. al., 2004
ConclusionsConclusions
• 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