New Drug Development and Review Yeong-Liang Lin, MD, MS Center for Drug Evaluation
Information <ul><li>International Conference on Harmonization  </li></ul><ul><li>The US Food and Drug Administration  </li...
Drug Development <ul><li>Discovery </li></ul><ul><li>Development </li></ul><ul><li>Chemistry, manufacturing and controls <...
CMC <ul><li>Drug substance </li></ul><ul><li>Drug product </li></ul>
Drug Substance <ul><li>Nomenclature </li></ul><ul><li>Structure </li></ul><ul><li>General properties: appearance, color, m...
Manufacturing Process <ul><li>Manufacturing steps: reaction, extraction, isolation, purification, processing </li></ul><ul...
Process Controls <ul><li>Controls during production to monitor the process to ensure that drug substance will conform to i...
Characterization <ul><li>Elucidation of structure: chemical structure elucidated using mass spectrometry, nuclear magnetic...
Control of Substance <ul><li>Specification </li></ul><ul><li>Analytical procedures </li></ul><ul><li>Validation of analyti...
Drug Product <ul><li>Excipient </li></ul><ul><li>Formulation development: proposed route of administration, release mechan...
Pharmacology  <ul><li>Studies to examine the primary therapeutic effects of a drug candidate </li></ul>
Safety Pharmacology <ul><li>Detect undesirable properties relevant to human safety, evaluate adverse effects and investiga...
Toxicology Studies <ul><li>Carcinogenicity studies </li></ul><ul><li>Genotoxicity studies </li></ul><ul><li>Reproductive t...
Toxicology  <ul><li>Acute, sub-chronic and chronic toxicity at the proposed site of exposure </li></ul><ul><li>At least th...
Toxicology Studies <ul><li>Acute toxicity studies </li></ul><ul><li>Characterize the spectrum of toxicity </li></ul><ul><l...
Biopharmaceutic Studies <ul><li>Background studies </li></ul><ul><li>Bioavailability studies </li></ul><ul><li>Pharmacokin...
Background Studies <ul><li>Absorption, distribution, metabolism and elimination studies </li></ul><ul><li>Carried out in a...
Bioavailability Studies <ul><li>Measure the rate and extent to which an active ingredient is absorbed from a drug product ...
Pharmacokinetic Studies <ul><li>Define the time course of drug and major metabolite concentrations in blood and other body...
In Vitro Studies <ul><li>Define the release rate of a drug from the dosage form </li></ul><ul><li>Characterization of a do...
Drug Interaction Studies <ul><li>Cytochrome P-450 superfamily </li></ul><ul><li>Substrate for metabolic pathways </li></ul...
PK in Patients with Organ Impairment <ul><li>Patients with impaired hepatic function </li></ul><ul><li>Patients with impai...
Clinical Trial <ul><li>Phase I, II, III, IV </li></ul>
Phase I <ul><li>Normal healthy volunteers, in general </li></ul><ul><li>Determine toxicity, safety and early evidence of e...
Phase II <ul><li>Controlled clinical trials </li></ul><ul><li>Demonstrate effectiveness and relative safety </li></ul><ul>...
Phase III <ul><li>Expended controlled clinical trials </li></ul><ul><li>Evidence of effectiveness for specific indications...
Phase IV <ul><li>Additional studies to elucidate the incidence of adverse reactions after drug approval </li></ul><ul><li>...
Ethnic Factor <ul><li>International Conference on Harmonization guidance E5 Ethnic Factors in the Acceptability of Foreign...
Steps <ul><li>Evaluate complete clinical data package </li></ul><ul><li>Adequate characterization of pharmacokinetics, pha...
Characterization in Foreign Populations <ul><li>Clinical trials conducted according to regulatory standards in the new reg...
Characterization in the New Population <ul><li>Influence by ethnic factors </li></ul><ul><li>- Extrinsic ethnic factors </...
Intrinsic Factors <ul><li>Linear pharmacokinetics? </li></ul><ul><li>Flat pharmacodynamic curve in the range of recommende...
Extrinsic Factors <ul><li>High likelihood of use with multiple medications? </li></ul><ul><li>High likelihood of inappropr...
Foreign Data Unacceptable <ul><li>If foreign data not acceptable to apply directly to the new population,  </li></ul><ul><...
Potential Hurdles <ul><li>Inadequate efficacy </li></ul><ul><li>Safety issues </li></ul><ul><li>- Hepatotoxicity </li></ul...
Review of Hepatotoxicity <ul><li>Cases of liver failure before drug approval </li></ul><ul><li>Clinical meaningful elevati...
Review of QT Prolongation <ul><li>In vitro I kr  Assay: effects on ion channel </li></ul><ul><li>In vitro QT assay: ventri...
Conclusion <ul><li>Quality </li></ul><ul><li>Preclinical safety information </li></ul><ul><li>Adequate efficacy evidence <...
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New Drug Development And Review

  1. 1. New Drug Development and Review Yeong-Liang Lin, MD, MS Center for Drug Evaluation
  2. 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. 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. 4. CMC <ul><li>Drug substance </li></ul><ul><li>Drug product </li></ul>
  5. 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. 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. 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. 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. 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. 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. 11. Pharmacology <ul><li>Studies to examine the primary therapeutic effects of a drug candidate </li></ul>
  12. 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. 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. 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. 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. 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. 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. 18. Bioavailability Studies <ul><li>Measure the rate and extent to which an active ingredient is absorbed from a drug product </li></ul>
  19. 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. 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. 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. 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. 23. Clinical Trial <ul><li>Phase I, II, III, IV </li></ul>
  24. 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. 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. 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. 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. 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. 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. 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. 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. 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. 33. Extrinsic Factors <ul><li>High likelihood of use with multiple medications? </li></ul><ul><li>High likelihood of inappropriate use? </li></ul>
  34. 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. 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. 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. 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. 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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