Assessing Drug Safety and ADHD Medications, Including Atomoxetine

A. J. Allen, M.D., Ph.D.Child Psychiatrist, Pharmacologist Global Medical Director – StratteraEli Lilly and Company

Thoughts re: Patients, Families, and Clinicians

• Re: public comments• ADHD is a real medical condition with

significant morbidity and needs treatment• All treatment options have benefits and risks,

some expected and some unexpected– This includes medications, non-medication

interventions, and no treatment• Goal should be to inform patients and families

of both benefits and risks so that they can decide the best treatment option for them. – Goal is NOT to scare patients/families so much that

they are afraid to seek treatment– Goal is NOT to deny or prevent treatment out of fear

Thoughts re: Patients, Families, and Clinicians (Continued)

• Clinicians know their individual patients and are in the best position to direct their treatment as needed – don’t tie their hands with a one size fits all solution

• Need for more research of ADHD, its causes and treatment options

• Access to mental health care for children and families is already a major concern, don’t make that problem worse

“Scientific knowledge is a body of statements of varying degrees of certainty – some more unsure, some nearly

sure, none absolutely certain.

Richard P. Feynman, Ph.D.

The Pleasure of Finding Things Out

Chapter 6, The Value of Science

Atomoxetine (ATX) ADHD Clinical Trials

• Most data are from trials initiated prior to first marketing approval, so no exclusion for ATX non-responders or patients unable to tolerate ATX in clinical practice

• No “run in” trial to select for ATX responders• With the exception of trials that included a

stimulant, trials allowed stimulant non-responders or patients unable to tolerate stimulants in clinical practice

Atomoxetine (ATX) ADHD Clinical Trials (Continued)

• ADHD trials required diagnosis of ADHD (any subtype) and minimum symptom severity at baseline

• Most pediatric trials allowed common ADHD comorbidities: oppositional defiant disorder, anxiety, depression, tics– Exception: trials including a stimulant excluded

labeled contraindications, as well as those with history of poor response to stimulants

– 3 trials required comorbidities: 1 anxiety, 1 depression, 1 tics

• Adult trials excluded anxiety, depression• All trials excluded patients who had seizures,

psychosis, mania, or who were suicidal

Clinical Trial Data (All Ages)DB Exposure in patient-yrs (N,

time)

OL Exposure in patient-yrs (N,

days)

Total (DB+OL) Exposure in patient-yrs

MPH products 152.5 (2256, 25 days)

2147.0 (4628, 169 days)

2299.4

Amphetamine Products

77.2 (1236, 23 days)

1767.5 (5177, 125 days)

1844.7

Modafinil 85.5 (772, 40 days)

383.5 (924, 152 days)

469.0

Total Above 3 315.2 (4264, 27 days)

4298.0 (10,729, 146 days)

4613.1

Atomoxetine 654.9 (2459, 97 days)

5095.3 (5270, 353 days)

5750.1

Derived From: Table 3, Mosholder, FDA Report PID: D060163, March 3, 2006

Disclosure of Lilly Clinical Trial Data

• Required by our Principles of Medical Research and occurs via– Presentations and posters at scientific

meetings– Publications in peer-reviewed, scientific

journals– Clinical trial registry: www.lillytrials.com

Lilly Code of Business Conduct

• “Lilly is committed to maintaining the quality and safety of its products. Therefore, all employees are required to report the following:

Adverse Event - any undesirable medical occurrence in a patient administered a Lilly product (drug or device), including side effects already listed in the package insert.”

Reporter type for atomoxetine spontaneous AE reports

Consumer, 58%

Other, 1%

HCP via Company Rep., 26%

HCP, 15%

Most AE reports from consumers come through The Lilly Answer Center (1-800-LillyRx) Notes: All atomoxetine spontaneous cases through 3/14/2006. HCP = health care professional.

Some Limitations of Post-Marketing Adverse Event Reports

• Differences between companies in methods and efficiency for collecting events

• Medication history, clinician experience and comfort affect reporting rates

• Many reports that are received are sketchy or lack important information

Some Limitations of Post-Marketing Adverse Event Reports (continued)

• Lack of control group– Especially important in pediatric population

due to developmental changes

• Confounded by multiple factors– Coexisting diagnoses– Other treatments (meds, psychotherapy, etc.)– Psychosocial factors (e.g., academic

problems)– Life events (e.g., death of a loved one)

Putting Risks in Context: Odds of Death Due to Injury, US, 2002

Type of Accident or Manner of Injury One Year Odds

MVA: Pedestrian 1 in 47,273

MVA: Car Occupant 1 in 17,625

Airplane Accident 1 in 440,951

Fall (any type) 1 in 17,712

Accidental drowning and submersion 1 in 83,534

Due to Smoke or Fire 1 in 91,149

Lightning 1 in 4,362,746

Intentional Self-Harm (suicide) 1 in 9,096

Assault by Firearm 1 in 24,342

National Safety Council: http://www.nsc.org/lrs/statinfo/odds.htm

Bottom Line Regarding Post-Marketing Adverse Events

• Important, but imperfect pharmacovigilance tool

• Efficiency of collecting events differs depending on medication and company

• Cases often difficult to assess• Need to compare to background rate of

events in relevant population • Need to put risks in context

Pharmacology

Binding Affinity of Atomoxetine & Psychostimulants for the NE & DA Transporters

CompoundNET

Ki, nM, meanDAT

Ki, nM, meanRatio

DAT/NET

Atomoxetine 3.5 (5a, 2.0e) 1266 (1451a, 1080e) 362

Methylphenidate 427 (339a, 514b) 46 (34a, 84b, 21c) 0.11

D-Amphetamine 257d 190c 0.7

aBymaster et al. 2002 bGatley et al. 1996 cPristupa et al. 1994 dCheetham et al. 1996 eTatsumi et al. 1997

Effects of Atomoxetine (Effects of Atomoxetine (●●) or Vehicle () or Vehicle (oo) on ) on Locomotor Activity in Sham-lesioned Locomotor Activity in Sham-lesioned ((nn=13) and 6-OHDA-lesioned (=13) and 6-OHDA-lesioned (nn=13) rats=13) rats

From Moran-Gates et al., Int J Neuropsychopharmacol 2005; 8(3)439–444.

Subject Rating: “Do you like the drug effect you are feeling now?”

0

5

10

15

20

25

30

35

40

PBO MPH90 PH60 D100 D200 A45 A90 A180

Mean

Sco

re +

/- S

E

****

*P<.05, ***p<.001.Note: MPH90 was significantly different from A45, A90, and A180 (p<.001).

PBO: placeboMPH90: methylphenidate, 90 mgPH60: phentermine, 60 mgD100: desipramine, 100 mgD200: desipramine, 200 mgA45: atomoxetine, 45 mgA90: atomoxetine, 90 mgA180: atomoxetine, 180 mg

From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

Morphine-Benzedrine Group Scale

0

2

4

6

8

10

12

14

16

18

PBO MPH90 PH60 D100 D200 A45 A90 A180

Mea

n S

core

+/-

SE

***p<.001.Note: MPH90 was significantly different from A45, A90, and A180 (p<.001).

*** ***PBO: placeboMPH90: methylphenidate, 90 mgPH60: phentermine, 60 mgD100: desipramine, 100 mgD200: desipramine, 200 mgA45: atomoxetine, 45 mgA90: atomoxetine, 90 mgA180: atomoxetine, 180 mg

From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

Cardiovascular

Changes in Heart Rate and Systolic BP 1.5 h Post Dose

-6-4-202468

10121416

PBO MPH90 PH60 D100 D200 A45 A90 A180

Mea

n C

han

ge

(bp

m) Supine

Ortho

PBO: placeboMPH90: methylphenidate, 90 mgPH60: phentermine, 60 mgD100: desipramine, 100 mgD200: desipramine, 200 mgA45: atomoxetine, 45 mgA90: atomoxetine, 90 mgA180: atomoxetine, 180 mg

From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

Heart Rate

Systolic BP

Suicidal Ideation or Behaviors

General Methodology for Conducting Meta-Analyses of Psychiatric AEs

• Text string search of database fields for visits in window of time

• Remove clear false positive “hits”• Prepare data for review

– Raw data (line listings)– One page patient summaries (OPPS)

• Health care professionals blind to treatment assess cases and categorize using predefined criteria (for suicidality, all are variants of Columbia Univ. criteria)

• Statistical analysis of categorized cases

Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Placebo Using

FDA Methods

Risk ratio.009632 1 103.824

Study % WeightRisk ratio(95% CI)

2.86 (0.12,68.99)HFBD 17.6

1.19 (0.05,28.96)LYAC 24.6

2.84 (0.12,68.70)LYAS 17.6

5.06 (0.25,103.82)LYAT 17.1

1.44 (0.06,34.99)LYCC 23.2

HFBK 0.0(n.a.)

LYAW 0.0(n.a)

LYAX 0.0(n.a.)

LYBG 0.0(n.a.)

LYBH 0.0(n.a.)

LYBI 0.0(n.a.)

LYBP 0.0(n.a.)

2.49 (0.64,9.78)Overall (95% CI)

---------------------- disadvantage active drug =>

Overall Risk ratio (95% CI)2.49 (.64, 9.78; p=.190)

-1 potential case

-1 potential case

-1 potential case

-2 potential cases

-1 potential case

- No cases

- No cases

- No cases

- No cases

- No cases

- No cases

- No cases

Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Methylphenidate Using FDA Methods

Risk ratio.01303 1 76.7435

Study % WeightRisk ratio(95% CI)

0.95 (0.04,22.56)HFBD 32.8

0.31 (0.01,7.43)LYAV 67.2

HFBK 0.0(n.a.)

LYBI 0.0(n.a.)

LYBR 0.0(n.a.)

0.52 (0.06,4.54)Overall (95% CI)

Risk ratio.01303 1 76.7435

Study % WeightRisk ratio(95% CI)

0.95 (0.04,22.56)HFBD 32.8

0.31 (0.01,7.43)LYAV 67.2

HFBK 0.0(n.a.)

LYBI 0.0(n.a.)

LYBR 0.0(n.a.)

0.52 (0.06,4.54)Overall (95% CI)

-----------------------> Disadvantage Atomoxetine

1 case

1 case

Suicidal Ideation or Behaviors Analysis Summary

• Suicidal ideation or behaviors were uncommon in atomoxetine-treated pediatric patients with most categorized as “suicidal ideation.”– Incidence of suicidal ideation was statistically greater

in atomoxetine-treated pediatric patients compared with placebo.

• The risk of suicidal ideation or behaviors with atomoxetine was not significantly different from that seen with methylphenidate (MHRR=0.52, 95% CI: 0.06, 4.54).

• Data does not demonstrate increased risk for suicidal ideation or behaviors in adults taking atomoxetine for ADHD.

• Label change (black box warning and medication guide) has been implemented.

Psychosis/Mania

General Methodology for Conducting Meta-Analyses of Psychiatric AEs

• Text string search of database fields for visits in window of time

• Remove clear false positive “hits”Remove clear false positive “hits”• Prepare data for reviewPrepare data for review

– Raw data (line listings)Raw data (line listings)– One page patient summaries (OPPS)One page patient summaries (OPPS)

• Health care professionals blind to treatment Health care professionals blind to treatment assess cases and categorize using assess cases and categorize using predefined criteria (for suicidality, all are predefined criteria (for suicidality, all are variants of Columbia Univ. criteria)variants of Columbia Univ. criteria)

• Statistical analysis of categorized cases

Some Phenomena That May Be Reported Clinically as Hallucinations in Young Children,

But that Are NOT Psychosis/Mania

• Imaginary friends• Hypnagognic hallucinations• Auras associated with migraine headaches• Images of loved ones who have died• Some obsessive thoughts in OCD• Flashbacks in PTSD• Other sensory phenomena (e.g., scary

images from horror movies)

Psychosis/Mania Events

• Patient 2• 12 yr M• Diagnoses: ADHD, Oppositional Defiant Disorder• ATX dose: 0.70 mg/kg/day• Time to onset: 2 days• Event: “Hallucinations, seeing things,” mild severity, 1

day duration• Other Events: Intermittent headaches (mild), Decreased

appetite (moderate), Nausea (mild), Tiredness (mild), mood swings (moderate), decreased sleep (mild), clouded thinking (moderate), mouth sores (mild).

• Outcome: Discontinued due to Lack of Efficacy at day 346.

Psychosis/Mania Events

• Patient 4– 9 yr M– Diagnoses: ADHD, Oppositional Defiant Disorder– ATX dose: 35 mg (1.16 mg/kg/day)– Time to onset: 212 days– Event: “Psychosis,” severe severity, unknown

duration– Other Events: blood in urine, knot in groin region,

knot above right eye, sore throat. Patient was sexually assaulted earlier in the study.

– Outcome: Discontinued from study and hospitalized due to this severe adverse event.

Trial in ADHD with Comorbid DepressionTreatment-Emergent Mania:

YMRS Total Score

• Treatment-emergent mania defined as YMRS total score <15 at baseline and 15 postbaseline.

• At baseline, 5 patients in the ATX group and 2 patients in the PBO group had YMRS scores >15. At endpoint, all but 1 patient in the ATX group had YMRS scores <15.

n %

Atomoxetine, N=68 2 2.9

Placebo, N=67 2 3.0

From Bangs et al. Poster presented at: The 45th Annual Meeting of the New Clinical Drug Evaluation Unit; June 6–9, 2005; Boca Raton, Fla.

Case Series: Atomoxetine Use in Children

with Bipolar Disorder & Comorbid ADHD

• 7 outpatients w/ pediatric BPD and comorbid ADHD• Treated w/ ATX; all but 1 also receiving mood

stabilizers• All but 1 showed significant improvement in ADHD

Sx severity• No episodes of hypomania or mania during Rx• AEs included sedation, nausea, decreased appetite• Conclusion: “ATX may be a safe and effective

treatment for ADHD in conjunction w/ mood stabilizers in children w/ BPD.”

From Hah & Chang, J Child Adolesc Psychopharmacol 2005; 15(6): 996-1004.

Psychosis/Mania Summary• Clinician review of pediatric cases identified via text string

search of the double-blind clinical trial adverse event database found that only 1 of 4 cases appeared to be true psychosis/mania and resulted in discontinuation of treatment due to the adverse event, but that case was confounded by a history of sexual assault– Event context, duration and/or severity were important

considerations in evaluating cases• In double-blind, placebo-controlled trial for pediatric ADHD

patients with comorbid depression, equal number of treatment emergent mania cases in ATX and placebo treated groups as assessed by YMRS

• The literature suggests that ADHD meds can benefit some patients with ADHD and comorbid pediatric bipolar disorder

Aggression/Hostility

Aggression/Hostility Analysis Summary

• Events were generally infrequent during these trials.• Majority of events were isolated reports of non-specific

aggression and did not result in discontinuation of medication

• Children and adolescents treated with atomoxetine showed a potentially higher risk of aggression or hostility events based on a numerically (but not statistically significantly) higher risk compared with placebo (MHRR=1.33, 95% CI: 0.67, 2.64).

• The risk of hostility or aggression events with atomoxetine was not significantly different from that seen with methylphenidate (MHRR=0.96, 95% CI: 0.29, 3.19).

• Children and adolescents taking atomoxetine for ADHD should be monitored closely for the emergence or worsening of aggressive behavior or hostility.

Conclusion: Lilly Key Points• ADHD is a real medical condition with significant

morbidity and needs treatment• Put benefits and risks of all treatment options in

context• Inform patients/families, but don’t try to scare them

and don’t limit access out of fear• Clinicians know their individual patients and are in the

best position to direct their treatment as needed• Strattera (atomoxetine) is generally safe and effective

for the treatment of ADHD• Lilly is committed to continued study of Strattera’s

benefits and risks, and to appropriate labeling

QUESTIONS?