Challenges and Considerations

1

• Challenges and Considerations
• Victor M. Santana, M.D.

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Drug Development in Children

• Research implications
• regulatory implications

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Drug Development in Pediatrics

• Research Regulatory
• advancement of data to support
• scientific knowledge indications
• pediatric oncology practice safety
• research trials are the medical practice
• standard of care

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Facts Research Implications

• Many more agents can be evaluated in Phase I
  trials in adults
• Even fewer new agents can be evaluated in Phase
  II trials in children
• For most solid tumors of children, only one Phase
  III study can be done every 4-5 years

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Thus Research Implications

• Need to prioritize approaches most likely to be
  successful when evaluated in children
• Prioritization based on
• successful approaches in adults
• compelling pre-clinical rationale
• patient population

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However, compelling need to obtain useful but
limited data in children

• e.g. the MTD, pharmacokinetics and dynamics
  different in children than adults
• (Taxol, teniposide)
• e.g. glucuronidation different in babies

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Are adult and pediatric solid tumors similar or
intrinsically different and why should we care?

• limited opportunities to test new agents in
  children
• making the regulatory mandate practical and
  likely to advance availability of new agents for
  children
• phenotypically tumors may be the same
  osteosarcoma e.g.
• genotypic characteristics or ontogeny may be very
  similar e.g. neuroblastic tumors

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Under which criteria should diseases be
considered the same (similar enough) in adults
and in children?

• differences similarities in biology
  (pathogenesis what creates the disease
  phenotype?)
• differences similarities in host (determinants of
  drug metabolism and toxicity)

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Integrating Factors that Determine Toxicity and
Response

• Tumor Biology Host Factors
• progression/malignant host susceptibility
• transformation
• accumulation of transforming carcinogenic
  exposure
• mutations
• cancer predisposition
• loss of DNA repair/genomic syndromes
• caretakers
• failure of apoptosis drug metabolism/
• enzyme polymorphisms
• drug resistance