Endpoints for Pediatric Brain Tumors December 6, 2006 meeting of the Pediatric Subcommittee to ODAC

1. Endpoints for Pediatric Brain TumorsDecember 6, 2006 meeting of the Pediatric Subcommittee to ODAC Karen D. Weiss, M.D. Deputy Director Office of Oncology Drug Products

2. Pediatric Brain Tumors Pediatric Oncology General Pediatrics General Oncology

3. GeneralPediatrics

4. Pathways to Pediatric Data for Regulatory Purposes • Drug intended for a pediatric disease • Drug approved for disease in adults • Pediatric Research Equity Act (PREA) • Disease occurs in children & adults • Best Pharmaceuticals for Children Act (BPCA) • May or may NOT be for adult indication

5. PREA Required, no $ Orphan indications exempt Drug/indication under development Drugs and Biologicals Trigger – application Results confidential if not approved Usual safety reporting BPCA • Voluntary, incentives • Includes orphan indication • Studies on whole moiety, & other indications • Applies only to drugs • Trigger – WR • Results posted regardless of approval • Safety data 1 year later

6. Challenges in Pediatric Drug Development • Extrapolation of adult data to children • Differences in pathophysiology despite ‘same’ disease • Differences in pK, ADME - degree of organ maturation • Outcome measures • Differences across the pediatric age groups • Include relevant age groups in studies • Procedures/sampling: blood volumes, diagnostic vs research procedures • Formulations • Ethical considerations: consent, assent, permission • Sample size considerations

7. General Oncology General Pediatrics Endpoints

8. Types of Approvals • Regular approval (RA) • Direct measure of clinical benefit • Longer life • Improved symptoms • Accepted surrogate • Accelerated approval (AA) • Surrogate reasonably likely to predict clinical benefit

9. Survival Time from randomization to death • Strengths • Unambiguous • Unbiased • Precise • Limitations • Requires large sample size, long follow-up • Cross-over therapy may confound effect • Trial design considerations • Need a randomized control group

10. Progression-Free Survival Time from randomization to progressive disease or death • Strengths • Smaller size & shorter follow-up than for survival • Differences not obscured by secondary therapy • Limitations • Methods to determine progression • Potential for bias • Trial design considerations • Randomized, blinded trial (or independent and masked radiographic review panel) • Evaluate - all patients using same tool(s) schedules

11. Response Rate • Strengths • Tumor shrinkage generally evidence of drug effect • Limitations • Reliable methods to measure? • Clinical meaning? • Need for durability component • Trial design considerations • Can establish in single arm trial • Definition: CR vs. CR + PR [ORR]

12. Endpoints Project – Guidances • General • Disease specific: • Colon • Lung • Prostate • Ovarian • Multiple Myeloma • Acute leukemia • Brain tumors

13. Pediatric Oncology General Pediatrics General Oncology

14. Pediatric Oncology I • Many adult cancers do not occur in children • Ability to extrapolate from adult data currently limited • May increase when/if greater understanding of tumorigenesis/drug mechanism of action • e.g., CML and TK inhibitors, EGFR expression, etc. • Very small patient populations; orphan indications • Studies may be difficult to enroll/long time to complete • Competing priorities • Impact of BPCA – information in drug labels

15. Pediatric Oncology II • Same approval mechanisms (RA and AA) • Same efficacy endpoints (survival, PFS, etc.) • Acute Leukemia workshop – June 2005 • Included pediatric ALL and AML • Brain tumor workshop – January 2006 • Did not address unique issues related to children with brain tumors, e.g., • Heterogeneity of the tumor • Differences across range of ages • Genesis for today’s meeting

16. Pediatric Brain Tumors Pediatric Oncology General Pediatrics General Oncology

17. Pediatric Brain Tumors • Many drugs used to treat children with brain tumors • ‘Older’ drugs • ‘Off label’ • Moving forward – study of new agents • I0 goal: identify and license effective drugs, advance the field • 20 goal: enhance pediatric information in the label

18. Pediatric Use:   TEMODAR effectiveness in children has not been demonstrated. TEMODAR Capsules have been studied in 2 open label Phase 2 studies in pediatric patients (age 3-18 years). “….29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had failed surgery and radiation therapy, while 31% also failed chemotherapy. In a second Phase 2 open label study...... 122 patients were enrolled, including medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9) and non-CNS tumors (9). The TEMODAR toxicity profile in children is similar to adults.

19. Meeting Agenda • Presentations: • Regulatory background – • Issues in non-inferiority designs • Summary of January 2006 workshop • Biology of pediatric brain tumors • Summary of COG experience • Issues in neuro-cognitive assessments • Open Public Hearing • Discussion

20. Discussion Topics • Value/pitfalls of developing risk based categories • Possible patient and disease related factors to consider for such categorization • Primary efficacy outcomes for licensure • Role and timing of radiographic/clinical measures • Neurological toxicity • What, how, and when to assess • Potential settings for non-inferiority studies • e.g, agents intended to reduce toxicity while maintaining efficacy