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

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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

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Pediatric Brain Tumors
Pediatric Oncology
General Pediatrics
General Oncology
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General Pediatrics
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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

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• 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

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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

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General Oncology
General Pediatrics
Endpoints
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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

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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

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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

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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

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Endpoints Project Guidances

• General
• Disease specific
• Colon
• Lung
• Prostate
• Ovarian
• Multiple Myeloma
• Acute leukemia
• Brain tumors

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Pediatric Oncology
General Pediatrics
General Oncology
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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

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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 todays meeting

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Pediatric Brain Tumors
Pediatric Oncology
General Pediatrics
General Oncology
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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

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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 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

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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