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Main Topics Discussed in the Last Meeting

Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science Meeting April 22-23. Quantitative risk analysis using exposure-response for determining dose adjustment for special populations Peter I. Lee, PhD Associate Director, Pharmacometrics

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Main Topics Discussed in the Last Meeting

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  1. Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science Meeting April 22-23 Quantitative risk analysis using exposure-response for determining dose adjustment for special populations Peter I. Lee, PhD Associate Director, Pharmacometrics Office of Clinical Pharmacology and Biopharmaceutics

  2. Main Topics Discussed in the Last Meeting • A standardized approach for evaluating the need of dose adjustment in special populations using exposure-response information. • A regulatory decision tree for dose adjustment recommendations. • Potential applications of utility function for risk and benefit assessment.

  3. Topics for This Session • Examples of standardized approach for using exposure-response information to adjust doses in special populations. • Population PK/PD approach for evaluating needs of dose adjustment in special populations. • An example of applying utility function for optimal dosing strategy.

  4. Background Information:Dose Adjustments in Special Populations • NDAs may contain up to 20 or more clinical pharmacology studies. • Intrinsic/extrinsic factors result in increases or decreases in exposure due to change in pharmacokinetics. • Need a consistent approach to determine dosing adjustment in special populations.

  5. An Example of Changes in Exposure Due to Intrinsic and Extrinsic Factors:When Should Dose be Adjusted ? Difference in AUC Change in AUC

  6. Issues Related to Dosing Adjustment in Drug Labels of NDA Submissions • Inconsistency in dosing adjustments is frequently seen in initial label language of NDA submissions. • Exposure-response information needed for rational dosing adjustment is sometimes incomplete or unavailable in the NDAs. • Additional exposure-response analyses are usually required and conducted by FDA reviewers to address questions of dosing adjustments. • Standard for analyzing and interpreting exposure-response data for safety and effectiveness assessments of drugs would be beneficial to decision-making.

  7. To Improve the Current Status, We Propose To ... • Develop and evaluate a standardized approach for reviewers and, possibly, industry to quantitatively assess the impact of exposure change on either safety or efficacy that result from change in pharmacokinetics due to intrinsic or extrinsic factors.

  8. Proposed Standardized Approach: Estimating the Probability of Response Frequency ref test ref test Frequency Exposure Response E+ Response Variable Probability of clinical significant response = Exposure

  9. Interpreting The Clinical Significance of PK Change • Observed data • PK in special populations • PK/PD relationship • Estimate the percentage (probability) in the patient population with the response > the clinically significant “critical value”. • Determine the “critical value” of response based on risk and benefit assessment of the drug therapy • case-by-case basis • utility functions

  10. Decision Tree for Dosing Adjustment Recommendations If the 90% CI of test/ref is within the default “no effect boundaries” y n No dose adjustment Is PK/PD available ? y n Whether the PK change is clinically significant based on E-R ? (Standardized Approach) n Refer to specific guidance to recommend labeling language Dosing adjustment, precaution, or warning y

  11. Examples to be Discussed Today • To illustrate the use of the proposed standardized approach for estimating the probability of toxicity in special populations to determine the need of dose adjustment. • To illustrate the potential utility of population analyses to obtain exposure-response information from large efficacy/safety trials. • To demonstrate a method for applying utility functions to optimize dosing strategy.

  12. Speakers in this Session • Dr. Nhi Nguyen, DPE1, OCPB • Dr. Jenny J. Zheng, DPE3, OCPB • Dr. He Sun, DPE2, OCPB • Dr. Mats Karlsson, Uppsala University

  13. Questions to the Committee • The standardized approach • Under what treatment circumstances (e.g.: intrinsic/extrinsic factors or therapeutic areas) would this standardized approach not be applicable ? • Does exposure-response differ between special and typical populations? If so, how can the differences be detected?

  14. Questions to the Committee (cont.) • Population PK/PD • What are the utility and general limitations of linking PK obtained from population analysis to response endpoints ? • What are the general considerations in E-R based dose adjustment for special populations ?

  15. Questions to the Committee (cont.) • Utility functions • Can the presented approach of utility function be generalized to other scenarios?

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