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Charge. Can one apply a Bayesian analysis where the a priori data comes from an adult patient population and the new data comes from a pediatric population? Dr. S. Hirschfeld, Halloween, 2001. What Can Bayesian Methods Do For Us?. FDA ODAC, Pediatric Subcommittee November 28, 2001

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Charge

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  1. Charge Can one apply a Bayesian analysis where the a priori data comes from an adult patient population and the new data comes from a pediatric population? Dr. S. Hirschfeld, Halloween, 2001

  2. What Can Bayesian Methods Do For Us? FDA ODAC, Pediatric Subcommittee November 28, 2001 Steven Goodman, MD, PhD Oncology Biostatistics Johns Hopkins University

  3. What are Bayesian Methods? Methods based on Bayes theorem a.k.a. Bayes factor

  4. What are Bayesian Methods? • Approaches that “combine information” of different types. • Provide a formal way to make statistical inferences from a clinical trial, incorporating prior knowledge. • A calculus of uncertainty. • A calculus of belief. • A calculus of evidence.

  5. In what settings have Bayesian designs/analyses been used? • Pharmacokinetics • Phase I - CRM • Phase II - Thall/Simon • Phase III - Spiegelhalter, Parmar, many others • Meta-analysis

  6. # of Bayes Articles in Medical Journals

  7. What Bayesian Methods Cannot Do • They cannot tell us, in the absence of empirical or biological information, how “alike” children and adults are, and how relevant adult information is for children.

  8. The Charge, Redux • Can one apply a Bayesian analysis where the a priori data comes from an adult patient population and the new data comes from a pediatric population? • Yes, but only if one makes an a priori judgment about how relevant the information from adults is for children.

  9. What information comes from adults? • Pharmacokinetics • Pharmacogenomics • Dose - Toxicity relationship • Types of toxicity • Frequency of toxicity / MTD • Efficacy • Covariate effects on all of above. • Uncertainty in all of above.

  10. What allows extrapolation to children? • Empirical comparisons • Knowledge of mechanism • Known adult-child biologic and clinical properties of analgous drugs. • Known sensitivity of children to specific toxicities.

  11. How is prior information represented? • Probability distributions on key parameters, expressing our “best guess” and degree of uncertainty. • Key parameters: • MTD • Response / Survival rate • Toxicity rate • Shape/slope of dose-toxicity curve • Pharmacokinetic parameters

  12. Bayesian Representation of Prior Knowledge

  13. Another view of prior information • Prior probability distributions are mathematically equivalent to information from N prior individuals. • “Made-up data.”

  14. Even weak knowledge = Subjects not needed • Confidence that cure rate lies within a 40% range (e.g. 20% -> 60%) corresponds to 25 patients worth of experimental information. • Confidence that cure rate lies within a 20% range (e.g. 20% -> 40%) corresponds to 100 patients worth of experimental information.

  15. What do these methods do for us? • Properly account for uncertainty/ knowledge in both previous and current experimental data. • Minimize the amount of information necessary from the current experiment - of value only if “priors” are reasonably accurate. • Promote research treatments that reflect, as closely as possible, our best guess about what would be best for the child based on all prior information. • Allow flexibility in design, because all Bayesian designs can be adaptive, i.e. responsive to accumulating data.

  16. What do these methods do for us? (cont.] • Encourage extremely valuable discussions about prior knowledge and uncertainty, and about goals of study. e.g. toxicity target in CRM. • Most “standard” approaches, used flexibly and with common sense, can become operationally indistinguishable from Bayesian ones, but this often requires more ad-hoc’ery, and lack of theoretical foundation.

  17. Charge Can one apply a Bayesian analysis where the a priori data comes from an adult patient population and the new data comes from a pediatric population?

  18. Final Answer • Yes, but only if the adult data is deemed relevant or informative. • More empirical studies of this relevance need to be conducted, and ongoing. • This may require incorporating additional endpoints and measurements into both adult and pediatric trials to facilitate this comparison.

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