Thoughts re: Patients, Families, and Clinicians

1. Assessing Drug Safety and ADHD Medications, Including AtomoxetineA. J. Allen, M.D., Ph.D.Child Psychiatrist, Pharmacologist Global Medical Director – StratteraEli Lilly and Company

2. 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

3. 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

4. “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

5. 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

6. 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

7. Clinical Trial Data (All Ages) Derived From: Table 3, Mosholder, FDA Report PID: D060163, March 3, 2006

8. 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

9. 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.”

10. Reporter type for atomoxetine spontaneous AE reports 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.

11. 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

12. 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)

13. Putting Risks in Context: Odds of Death Due to Injury, US, 2002 National Safety Council: http://www.nsc.org/lrs/statinfo/odds.htm

14. 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

15. Pharmacology

16. Binding Affinity of Atomoxetine & Psychostimulants for the NE & DA Transporters aBymaster et al. 2002 bGatley et al. 1996 cPristupa et al. 1994 dCheetham et al. 1996 eTatsumi et al. 1997

17. Effects of Atomoxetine (●) or Vehicle (o) on Locomotor Activity in Sham-lesioned (n=13) and 6-OHDA-lesioned (n=13) rats From Moran-Gates et al., Int J Neuropsychopharmacol 2005; 8(3)439–444.

18. Subject Rating: “Do you like the drug effect you are feeling now?” PBO: placebo MPH90: methylphenidate, 90 mg PH60: phentermine, 60 mg D100: desipramine, 100 mg D200: desipramine, 200 mg A45: atomoxetine, 45 mg A90: atomoxetine, 90 mg A180: atomoxetine, 180 mg *** * *P<.05, ***p<.001. Note: MPH90 was significantly different from A45, A90, and A180 (p<.001). From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

19. Morphine-Benzedrine Group Scale PBO: placebo MPH90: methylphenidate, 90 mg PH60: phentermine, 60 mg D100: desipramine, 100 mg D200: desipramine, 200 mg A45: atomoxetine, 45 mg A90: atomoxetine, 90 mg A180: atomoxetine, 180 mg *** *** ***p<.001. Note: MPH90 was significantly different from A45, A90, and A180 (p<.001). From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

20. Cardiovascular

21. Changes in Heart Rate and Systolic BP 1.5 h Post Dose PBO: placebo MPH90: methylphenidate, 90 mg PH60: phentermine, 60 mg D100: desipramine, 100 mg D200: desipramine, 200 mg A45: atomoxetine, 45 mg A90: atomoxetine, 90 mg A180: atomoxetine, 180 mg Heart Rate Systolic BP From Jasinski et al. Poster presented at: The XXIVth Congress of the Collegium Internationale Neuro-Psychopharmacologicum; June 20–24, 2004; Paris, France.

22. Suicidal Ideation or Behaviors

23. 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

24. -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 Overall Risk ratio (95% CI) 2.49 (.64, 9.78; p=.190) ---------------------- disadvantage active drug => Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Placebo Using FDA Methods

25. Suicidal Behavior or Ideation in Pediatric Trials: Risk Ratios for Atomoxetine vs Methylphenidate Using FDA Methods 1 case 1 case -----------------------> Disadvantage Atomoxetine

26. 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.

27. Psychosis/Mania

28. 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

29. 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)

30. 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.

31. 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.

32. 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. 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.

33. 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.

34. 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

35. Aggression/Hostility

36. 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.

37. 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?