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

2. 2 Pediatric Oncology Pediatric Brain Tumors General Pediatrics General Oncology

3. 3 General Pediatrics

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

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

6. 6 Challenges in Pediatric Drug Development Extrapolation of adult data to childrenExtrapolation 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 groupsDifferences across the pediatric age groups –Include relevant age groups in studies Procedures/sampling: blood volumes, diagnostic vs research proceduresProcedures/sampling: blood volumes, diagnostic vs research procedures FormulationsFormulations Ethical considerations: consent, assent, permissionEthical considerations: consent, assent, permission Sample size considerationsSample size considerations

7. 7 General Pediatrics General Oncology Endpoints

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

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

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

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

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

13. 13 Pediatric Oncology General Pediatrics General Oncology

14. 14 Pediatric Oncology I Many adult cancers do not occur in childrenMany 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.e.g., CML and TK inhibitors, EGFR expression, etc. Very small patient populations; orphan indicationsVery small patient populations; orphan indications –Studies may be difficult to enroll/long time to complete –Competing priorities Impact of BPCA – information in drug labelsImpact of BPCA – information in drug labels

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

16. 16 Pediatric Oncology Pediatric Brain Tumors General Pediatrics General Oncology

17. 17 Pediatric Brain Tumors Many drugs used to treat children with brain tumorsMany drugs used to treat children with brain tumors –‘Older’ drugs –‘Off label’ Moving forward – study of new agentsMoving forward – study of new agents –I 0 goal: identify and license effective drugs, advance the field –2 0 goal: enhance pediatric information in the label

18. 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. 19 Meeting Agenda Presentations: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 HearingOpen Public Hearing DiscussionDiscussion

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