Endpoints for Pediatric Brain TumorsEndpoints for Pediatric Brain Tumors

December 6, 2006 meeting of the December 6, 2006 meeting of the Pediatric Subcommittee to ODACPediatric Subcommittee to ODAC

Karen D. Weiss, M.D.Karen D. Weiss, M.D.Deputy DirectorDeputy Director

Office of Oncology Drug ProductsOffice of Oncology Drug Products

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Pediatric Oncology

Pediatric Brain Tumors

General Pediatrics General Oncology

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General Pediatrics

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Pathways to Pediatric Data for Pathways to Pediatric Data for Regulatory PurposesRegulatory Purposes

• Drug intended for a pediatric diseaseDrug intended for a pediatric disease• Drug approved for disease in adults Drug approved for disease in adults

– Pediatric Research Equity Act (PREA) Pediatric Research Equity Act (PREA) • Disease occurs in children & adultsDisease occurs in children & adults

– Best Pharmaceuticals for Children Act (BPCA) Best Pharmaceuticals for Children Act (BPCA) • May or may NOT be for adult indicationMay or may NOT be for adult indication

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BPCABPCA

• Voluntary, incentivesVoluntary, incentives• Includes orphan Includes orphan

indicationindication• Studies on whole Studies on whole

moiety, & other moiety, & other indicationsindications

• Applies only to drugsApplies only to drugs• Trigger – WRTrigger – WR• Results posted Results posted

regardless of approvalregardless of approval• Safety data 1 year laterSafety data 1 year later

PREAPREA

• Required, no $Required, no $• Orphan indications Orphan indications

exemptexempt• Drug/indication under Drug/indication under

developmentdevelopment• Drugs and Biologicals Drugs and Biologicals • Trigger – applicationTrigger – application• Results confidential if Results confidential if

not approvednot approved• Usual safety reportingUsual safety reporting

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Challenges in Pediatric Drug DevelopmentChallenges in Pediatric Drug Development• Extrapolation of adult data to children Extrapolation of adult data to children

– Differences in pathophysiology despite ‘same’ diseaseDifferences in pathophysiology despite ‘same’ disease– Differences in pK, ADME - degree of organ maturation Differences in pK, ADME - degree of organ maturation – Outcome measuresOutcome measures

• Differences across the pediatric age groupsDifferences across the pediatric age groups– Include relevant age groups in studiesInclude relevant age groups in studies

• Procedures/sampling: blood volumes, diagnostic vs Procedures/sampling: blood volumes, diagnostic vs research proceduresresearch procedures

• FormulationsFormulations• Ethical considerations: consent, assent, permission Ethical considerations: consent, assent, permission • Sample size considerationsSample size considerations

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General PediatricsGeneral Oncology

Endpoints

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Types of ApprovalsTypes of Approvals• Regular approval (RA)Regular approval (RA)

– Direct measure of clinical benefitDirect measure of clinical benefit• Longer lifeLonger life• Improved symptomsImproved symptoms

– Accepted surrogateAccepted surrogate

• Accelerated approval (AA)Accelerated approval (AA)– Surrogate Surrogate reasonably likelyreasonably likely to predict to predict

clinical benefitclinical benefit

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SurvivalSurvivalTime from randomization to deathTime from randomization to death

• StrengthsStrengths– UnambiguousUnambiguous– UnbiasedUnbiased– PrecisePrecise

• LimitationsLimitations– Requires large sample size, long follow-upRequires large sample size, long follow-up– Cross-over therapy may confound effectCross-over therapy may confound effect

• Trial design considerationsTrial design considerations– Need a randomized control groupNeed a randomized control group

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Progression-Free SurvivalProgression-Free SurvivalTime from randomization to progressive disease or deathTime from randomization to progressive disease or death

• StrengthsStrengths– Smaller size & shorter follow-up than for survivalSmaller size & shorter follow-up than for survival– Differences not obscured by secondary therapyDifferences not obscured by secondary therapy

• LimitationsLimitations– Methods to determine progressionMethods to determine progression– Potential for bias Potential for bias

• Trial design considerationsTrial design considerations– Randomized, blinded trial (or independent and masked Randomized, blinded trial (or independent and masked

radiographic review panel) radiographic review panel) – Evaluate - all patients using same tool(s) schedulesEvaluate - all patients using same tool(s) schedules

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Response RateResponse Rate• StrengthsStrengths

– Tumor shrinkage generally evidence of drug effect Tumor shrinkage generally evidence of drug effect

• LimitationsLimitations– Reliable methods to measure?Reliable methods to measure?– Clinical meaning?Clinical meaning?– Need for durability componentNeed for durability component

• Trial design considerationsTrial design considerations– Can establish in single arm trialCan establish in single arm trial– Definition: CR Definition: CR vsvs. CR + PR [ORR] . CR + PR [ORR]

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Endpoints Project – Guidances Endpoints Project – Guidances

• General General • Disease specific: Disease specific:

– ColonColon– LungLung– ProstateProstate– Ovarian Ovarian – Multiple MyelomaMultiple Myeloma– Acute leukemiaAcute leukemia– Brain tumorsBrain tumors

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Pediatric Oncology

General Pediatrics General Oncology

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Pediatric Oncology IPediatric 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 Ability to extrapolate from adult data currently limited – May increase when/if greater understanding of May increase when/if greater understanding of

tumorigenesis/drug mechanism of actiontumorigenesis/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 completeStudies may be difficult to enroll/long time to complete– Competing prioritiesCompeting priorities

• Impact of BPCA – information in drug labels Impact of BPCA – information in drug labels

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Pediatric Oncology IIPediatric 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 Included pediatric ALL and AML • Brain tumor workshop – January 2006Brain tumor workshop – January 2006

– Did not address unique issues related to children Did not address unique issues related to children with brain tumors, e.g., with brain tumors, e.g.,

• Heterogeneity of the tumor Heterogeneity of the tumor • Differences across range of agesDifferences across range of ages

– Genesis for today’s meetingGenesis for today’s meeting

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Pediatric Oncology

Pediatric Brain Tumors

General Pediatrics General Oncology

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Pediatric Brain TumorsPediatric Brain Tumors• Many drugs used to treat children with Many drugs used to treat children with

brain tumorsbrain tumors– ‘‘Older’ drugs Older’ drugs – ‘‘Off label’ Off label’

• Moving forward – study of new agentsMoving forward – study of new agents– II00 goal: identify and license effective drugs, goal: identify and license effective drugs,

advance the fieldadvance the field– 220 0 goal: enhance pediatric information in the goal: enhance pediatric information in the

labellabel

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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.

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Meeting AgendaMeeting Agenda• Presentations:Presentations:

– Regulatory background – Regulatory background – – Issues in non-inferiority designs Issues in non-inferiority designs – Summary of January 2006 workshopSummary of January 2006 workshop– Biology of pediatric brain tumorsBiology of pediatric brain tumors– Summary of COG experience Summary of COG experience – Issues in neuro-cognitive assessmentsIssues in neuro-cognitive assessments

• Open Public HearingOpen Public Hearing• DiscussionDiscussion

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Discussion TopicsDiscussion Topics• Value/pitfalls of developing risk based categories Value/pitfalls of developing risk based categories • Possible patient and disease related factors to Possible patient and disease related factors to

consider for such categorizationconsider for such categorization• Primary efficacy outcomes for licensurePrimary efficacy outcomes for licensure

– Role and timing of radiographic/clinical measures Role and timing of radiographic/clinical measures • Neurological toxicityNeurological toxicity

– What, how, and when to assessWhat, how, and when to assess• Potential settings for non-inferiority studies Potential settings for non-inferiority studies

– e.ge.g, agents intended to reduce toxicity while , agents intended to reduce toxicity while maintaining efficacy maintaining efficacy