1. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Pediatric Drug Development for Neuro-Psychiatric Diseases Yoshiaki Uyama, Ph.D. Pharmaceuticals and Medical Devices Agency (PMDA) Visiting Professor, Graduate School of Advanced Clinical Science, Chiba University Visiting Professor, Graduate School of Medicine, Nagoya University 1

2. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Examples of approved pediatric drugs in neurological/psychiatric diseases in Japan 2 Active IngredientTherapeuticsApproval Date Baclofen (Intrathecal Injection) Severe spasticity of cerebral or spinal origin Jan. 2007 Fentanyl InjectionPediatric dose approval for anesthesia and pain control Jul. 2007 Methylphenidate (Sustained release) Attention-Deficit/Hyperactivity Disorder (ADHD) Oct. 2007 Phenobarbital Injection Infantile convulsionOct. 2008 LamotriginePediatric dose approval for epilepsyOct. 2008 Onabotulinumtoxin ASpasm in cerebral palsyJan. 2009 AtomoxetineAttention-Deficit/Hyperactivity Disorder (ADHD) Apr. 2009 FosphenytoinSeizureJul. 2011 GabapentinPediatric dose approval for epilepsyJul. 2011

3. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Promoting pediatric drug developments in Japan Extension of re-evaluation period (the exclusive period) Normally 8 years for a new molecular entity Additional 2 years may be granted, if pediatric drug development plan is submitted and approved Example of the granted product Fluvoxamine, Paroxetine, Aripiprazole etc. 3

4. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency 4 Discussion Points in the review for neuropsychiatric drugs

5. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency 1. Study design Endpoint, Target patients, Dose/Administration, Active control, Sample size, Interim analysis etc. 2. Efficacy Clinical meaningfulness, Consistency, Factors affecting efficacy (Patient background, Pre-medication, Concomitant medication etc.) 3. Safety Serious adverse events and its causality, Profile of high risk patients, measures for risk management/prevention etc. General Discussion Points in the review for neuropsychiatric drugs 5

6. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Special discussion points in the review of pediatric drugs for neuropsychiatric disease Minimum age of patients who can take a drug Reliability of subjective endpoint Importance of evaluation by Parent/Teacher Training in advance Adverse effects for growth/development Weight, Stature, Endocrine system Long-term safety including suicide risk, dependence, abuse Risk management plan Educational programs for patients and parents 6

7. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Examples of the review for approved drugs 7

8. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Methylphenidate (CONCERTA ® ) for ADHD Placebo-controlled, randomized withdrawal study 8 Changes on total score of ADHD RS-IV-J (PARENT) ● Methylphenidate ○ Placebo LS mean±95% CI Evaluation Period http://www.info.pmda.go.jp/shinyaku/P200700052/800155000_21900AMX01770000_A100_1.pdf

9. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Discussion in the review of CONCERTA ® Effects of age and body-weight on PK Measures to promote optimal use of the drug Benefit/risk in patients over 13 years (not enrolled in clinical trials) Drug interruption during long-vacation Assessment reliability based on ADHD RS-IV-J Effects of gender and types of ADHD on efficacy Loss in stature and weight increase in long-term use Cardiovascular event, Risk of dependence and abuse, Suicide risk Risk management plans after approval 9 http://www.info.pmda.go.jp/shinyaku/P200700052/800155000_21900AMX01770000_A100_1.pdf

10. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Challenges in pediatric drug development 10

11. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Challenges in pediatric drug development 1.Difficulty to conduct placebo-controlled study Low feasibility due to reluctance for enrollment Parents Physician Uncertainty of placebo-response rate Effects of intervention by psychiatrist 11

12. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency 12 Example: Fluvoxamine for pediatric depression Placebo-controlled trial was conducted in Japanese pediatric patients with depression 3 years after starting the trial, the trial was discontinued What is happened? Only 69 % of target patient numbers (90/130 patients) was enrolled Independent monitoring committee recommended to discontinue the trial due to a lack of efficacy http://www.mhlw.go.jp/stf/shingi/2r98520000018x8g-att/2r98520000018xet.pdf

13. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Efficacy data of the trial in pediatric depression 13 Improvement Periods of JSIGH-D (17items) No superiority to placebo http://www.mhlw.go.jp/stf/shingi/2r98520000018x8g-att/2r98520000018xet.pdf

14. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency 14 Safety data of the trial in pediatric depression No death case in the trial 2 SAE, but no causality with the drug Major adverse event was nasopharyngitis, nausea, somnolence etc. Suicide related events was higher in placebo (6.71% (3/45) vs 20.0% (9/45)) Patient enrollment was very difficult Efficacy of fluvoxamine was not confirmed, possibly due to high placebo response rate No major safety concern was obtained http://www.mhlw.go.jp/stf/shingi/2r98520000018x8g-att/2r98520000018xet.pdf

15. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency 15 Other challenges in pediatric drug development 2.Pediatric psychiatrist is very few More training and education 3.Establishment of reliable endpoint specially designed for pediatric disease Score used in adults is not usually applicable 4.Education about clinical trials & drug developments to parents and school teachers as well as patients/physicians 5.Establishment of monitoring system for long-term follow-up of patients

16. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Future Direction 16 Drug development will be more globalized Good opportunity to work together in pediatric drug developments Let’s consider Global Drug Development To increase a feasibility of a trial in pediatric diseases To establish more appropriate strategy to develop a drug for children Do not miss a chance to develop/provide a drug to children in the world

17. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency - SMART Global - 17 Sharing data/experiences/knowledge globally Managing projects/issues globally Advancing regulatory science globally Respect for other idea/views globally Transparent process globally

18. ASENT/ISCTM, Feb 23 rd, 2012, Washington DC, USA Pharmaceuticals & Medical Devices Agency Information PMDA HOMEPAGE (English) http://www.pmda.go.jp/english/index.html E-mail: uyama-yoshiaki@pmda.go.jp Thank you for your attention 18