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Quantitative Risk/Benefit Analysis in Regulatory Decision Making

Quantitative Risk/Benefit Analysis in Regulatory Decision Making. B. Nhi Nguyen, Patrick Marroum & Joga Gobburu FDA / CDER / OCPB / DPE 1 Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee April 22, 2003. Gobburu & Sekar, Int.J.Clin.Pharm., 2002.

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Quantitative Risk/Benefit Analysis in Regulatory Decision Making

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  1. Quantitative Risk/Benefit Analysis in Regulatory Decision Making B. Nhi Nguyen, Patrick Marroum & Joga Gobburu FDA / CDER / OCPB / DPE 1 Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee April 22, 2003

  2. Gobburu & Sekar, Int.J.Clin.Pharm., 2002 Integration of Knowledge Benefit Risk Dose Ranging Studies Models Prob Benefit Risk

  3. Simulations

  4. Objective • Quantitate the risk / benefit of a drug Exposure - Effectiveness Model • Primary endpoint • Largest clinical trial, longest duration • Primary effectiveness endpoint & PK collected @ week 0, 2, 4 • Nominal doses: 0.5 mg bid, 1, 2, 4 mg qd

  5. Exposure - Risk Models • Adverse event data from all pivotal clinical trials • Focus: dizziness, edema, liver toxicity, palpitations, tachycardia, vertigo •  QTc • Ketoconazole 400 mg + drug 0.5 mg qd • ECGs - 0, 1, 2, 3, 4 h post dose • Up to 24 h of drug PK

  6. Exposure - Effectiveness Emax = 7.6 EC50 = 0.2 units 5 11 1 * Cmax  1 mg 4 mg 2 mg

  7. Exposure - QTc Prolongation 1 mg 2 mg 4 5 * (units)

  8. Probability of Tachycardia 50 kg 70 kg 0 1 2 6 *

  9. Special Population Studies

  10. Integration of ER Relationship + Keto + Gfj * * Concentration (units) Concentration (units) 50 kg 70 kg *

  11. Summary of Data Integration

  12. Conclusions • Weigh effectiveness and risks with review team • Know assumptions of models • Recommend conduct appropriate QT study • Explore wide concentration range • Collect QT data over 24 h

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