1. Outline Significance Definitions Challenges Next steps

2. Significance Quality of Life Safety Efficacy/potentially modifiable

3. Definitions What is neurocognition? Inter-related levels of investigation But need to be clear on what we are measuring

4. What to measure Depth vs breadth Inclusion criteria (make the most of each trial) Across age/ability; validation Multi-center: multiple cultures/languages FDA-requirements: clinical vs regulatory significance

5. Scientific Challenges Drug efficacy –Mouse models: translating from mouse to man –Predicting responders –When and how long to treat Placebo-controlled, double blind trials needed Side effects of drug –Risk/benefits in pediatric population Neurocognitive assessments –Dynamic measures within timeframe of trial –Standard battery across trials

6. Logistical challenges IRB and FDA requirements Multi-site enrollment for rare disorders Broad Infrastructure –Recruitment, Patient safety, Monitoring, Data management, Data analysis Funding

7. Next Steps - I Patient Based Outcome Measures In terms of FDA – f/u neuro-onco, epilepsy trials etc. Stratify by epilepsy Younger age/adults/more severely affected Sleep/depression/anxiety

8. Next Steps - II Off-label use Education- importance of neurocog clinical trials Biomarkers of cognition Funding