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New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
New Drug Development and Review
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New Drug Development and Review

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  • 1. New Drug Development and Review Yeong-Liang Lin, MD, MS Center for Drug Evaluation
  • 2. Information <ul><li>International Conference on Harmonization </li></ul><ul><li>The US Food and Drug Administration </li></ul><ul><li>EMEA </li></ul><ul><li>Taiwan Department of Health </li></ul><ul><li>Taiwan Center for Drug Evaluation </li></ul>
  • 3. Drug Development <ul><li>Discovery </li></ul><ul><li>Development </li></ul><ul><li>Chemistry, manufacturing and controls </li></ul><ul><li>Pharmacology </li></ul><ul><li>Toxicology </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Clinical trial </li></ul>
  • 4. CMC <ul><li>Drug substance </li></ul><ul><li>Drug product </li></ul>
  • 5. Drug Substance <ul><li>Nomenclature </li></ul><ul><li>Structure </li></ul><ul><li>General properties: appearance, color, melting or boiling point, solubility profile, solution PH, physical form </li></ul><ul><li>Manufacture: manufacturer, manufacturing process and control </li></ul>
  • 6. Manufacturing Process <ul><li>Manufacturing steps: reaction, extraction, isolation, purification, processing </li></ul><ul><li>Chemical structure of starting material, intermediate, reagent </li></ul><ul><li>Solvent and auxiliary material </li></ul><ul><li>Temperature, pH and pressure </li></ul><ul><li>Anticipated yield </li></ul>
  • 7. Process Controls <ul><li>Controls during production to monitor the process to ensure that drug substance will conform to its specification </li></ul><ul><li>Operating conditions: temperature, pH, pressure </li></ul><ul><li>Environmental conditions </li></ul><ul><li>In-process material test </li></ul>
  • 8. Characterization <ul><li>Elucidation of structure: chemical structure elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, crystallography </li></ul><ul><li>Impurity: organic, inorganic, residual solvent, heavy metal </li></ul>
  • 9. Control of Substance <ul><li>Specification </li></ul><ul><li>Analytical procedures </li></ul><ul><li>Validation of analytical procedures </li></ul><ul><li>Batch analyses </li></ul>
  • 10. Drug Product <ul><li>Excipient </li></ul><ul><li>Formulation development: proposed route of administration, release mechanism for modified release products, changes between the proposed commercial formulation and formulations used in clinical batches </li></ul>
  • 11. Pharmacology <ul><li>Studies to examine the primary therapeutic effects of a drug candidate </li></ul>
  • 12. Safety Pharmacology <ul><li>Detect undesirable properties relevant to human safety, evaluate adverse effects and investigate the mechanism of adverse effects </li></ul><ul><li>- Central nervous system </li></ul><ul><li>- Cardiovascular system </li></ul><ul><li>- Respiratory system </li></ul><ul><li>- Renal system </li></ul><ul><li>- Gastrointestinal system </li></ul>
  • 13. Toxicology Studies <ul><li>Carcinogenicity studies </li></ul><ul><li>Genotoxicity studies </li></ul><ul><li>Reproductive toxicity studies </li></ul><ul><li>Developmental toxicity studies </li></ul><ul><li>Local tolerance studies </li></ul>
  • 14. Toxicology <ul><li>Acute, sub-chronic and chronic toxicity at the proposed site of exposure </li></ul><ul><li>At least three dose levels with high dose showing frank toxicity and low dose showing no toxicity </li></ul><ul><li>Final formulation and study duration equal to or longer than the proposed duration of treatment in clinical trials </li></ul>
  • 15. Toxicology Studies <ul><li>Acute toxicity studies </li></ul><ul><li>Characterize the spectrum of toxicity </li></ul><ul><li>One dose and observed for 14 days </li></ul><ul><li>Measurements: signs and pathology </li></ul><ul><li>Repeated dose toxicity studies </li></ul><ul><li>Sub-acute or chronic studies </li></ul><ul><li>Observed for a period </li></ul>
  • 16. Biopharmaceutic Studies <ul><li>Background studies </li></ul><ul><li>Bioavailability studies </li></ul><ul><li>Pharmacokinetic studies </li></ul><ul><li>In vitro studies </li></ul>
  • 17. Background Studies <ul><li>Absorption, distribution, metabolism and elimination studies </li></ul><ul><li>Carried out in a few subjects </li></ul><ul><li>Guide early studies on humans </li></ul>
  • 18. Bioavailability Studies <ul><li>Measure the rate and extent to which an active ingredient is absorbed from a drug product </li></ul>
  • 19. Pharmacokinetic Studies <ul><li>Define the time course of drug and major metabolite concentrations in blood and other body compartments </li></ul><ul><li>Rate of drug absorption and delivery to systemic circulation </li></ul><ul><li>Changes in kinetic parameters with doses within the recommended dosing range </li></ul><ul><li>Influence of age, sex, race and disease states </li></ul>
  • 20. In Vitro Studies <ul><li>Define the release rate of a drug from the dosage form </li></ul><ul><li>Characterization of a dosage form </li></ul>
  • 21. Drug Interaction Studies <ul><li>Cytochrome P-450 superfamily </li></ul><ul><li>Substrate for metabolic pathways </li></ul><ul><li>Effects on other drugs </li></ul><ul><li>Positive results suggest the need for further clinical evaluation </li></ul>
  • 22. PK in Patients with Organ Impairment <ul><li>Patients with impaired hepatic function </li></ul><ul><li>Patients with impaired renal function </li></ul>
  • 23. Clinical Trial <ul><li>Phase I, II, III, IV </li></ul>
  • 24. Phase I <ul><li>Normal healthy volunteers, in general </li></ul><ul><li>Determine toxicity, safety and early evidence of effectiveness </li></ul><ul><li>The number of subjects is in the range of 20-80 </li></ul>
  • 25. Phase II <ul><li>Controlled clinical trials </li></ul><ul><li>Demonstrate effectiveness and relative safety </li></ul><ul><li>Number of subjects: seldom beyond 100-200 </li></ul>
  • 26. Phase III <ul><li>Expended controlled clinical trials </li></ul><ul><li>Evidence of effectiveness for specific indications and precise definition of drug-related adverse effects </li></ul><ul><li>Number of subjects: dependent on study hypothesis </li></ul>
  • 27. Phase IV <ul><li>Additional studies to elucidate the incidence of adverse reactions after drug approval </li></ul><ul><li>Large scale and long term </li></ul>
  • 28. Ethnic Factor <ul><li>International Conference on Harmonization guidance E5 Ethnic Factors in the Acceptability of Foreign Clinical Data </li></ul><ul><li>Waive local registration trial </li></ul><ul><li>Utilize foreign data to predict efficacy and safety in the new population </li></ul><ul><li>Avoid duplication of unnecessary clinical trials </li></ul>
  • 29. Steps <ul><li>Evaluate complete clinical data package </li></ul><ul><li>Adequate characterization of pharmacokinetics, pharmacodynamics, dose response, efficacy and safety in foreign populations </li></ul><ul><li>Characterization in a population relevant to the new region </li></ul>
  • 30. Characterization in Foreign Populations <ul><li>Clinical trials conducted according to regulatory standards in the new region </li></ul><ul><li>- Well controlled </li></ul><ul><li>- Appropriate endpoints </li></ul><ul><li>- Appropriate control drugs </li></ul>
  • 31. Characterization in the New Population <ul><li>Influence by ethnic factors </li></ul><ul><li>- Extrinsic ethnic factors </li></ul><ul><li>- Intrinsic ethnic factors </li></ul>
  • 32. Intrinsic Factors <ul><li>Linear pharmacokinetics? </li></ul><ul><li>Flat pharmacodynamic curve in the range of recommended dosage? </li></ul><ul><li>Wide therapeutic dose range? </li></ul><ul><li>Metabolism through multiple pathways? </li></ul><ul><li>High bioavailability? </li></ul><ul><li>Low protein binding? </li></ul>
  • 33. Extrinsic Factors <ul><li>High likelihood of use with multiple medications? </li></ul><ul><li>High likelihood of inappropriate use? </li></ul>
  • 34. Foreign Data Unacceptable <ul><li>If foreign data not acceptable to apply directly to the new population, </li></ul><ul><li>- local efficacy studies </li></ul><ul><li>- local pharmacokinetic studies </li></ul><ul><li>- local pharmacodynamic studies </li></ul><ul><li>- local safety studies </li></ul>
  • 35. Potential Hurdles <ul><li>Inadequate efficacy </li></ul><ul><li>Safety issues </li></ul><ul><li>- Hepatotoxicity </li></ul><ul><li>- QT prolongation </li></ul>
  • 36. Review of Hepatotoxicity <ul><li>Cases of liver failure before drug approval </li></ul><ul><li>Clinical meaningful elevations of aminotransferases </li></ul><ul><li>Combined jaundice and ALT elevations </li></ul><ul><li>Inadequate sample size to detect rare liver toxicity by pre-approval clinical trials </li></ul>
  • 37. Review of QT Prolongation <ul><li>In vitro I kr Assay: effects on ion channel </li></ul><ul><li>In vitro QT assay: ventricular repolarization </li></ul><ul><li>Drug interaction </li></ul><ul><li>Clinical trial: increase of the QT interval, increases greater than 60 msec, QT intervals longer than 500 msec </li></ul>
  • 38. Conclusion <ul><li>Quality </li></ul><ul><li>Preclinical safety information </li></ul><ul><li>Adequate efficacy evidence </li></ul><ul><li>Acceptable safety profile </li></ul><ul><li>Luck and Efforts! </li></ul>

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