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