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Drug Development

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Drug Development

  1. 1. ONCOLOGY Drug Development
  2. 2. ONCOLOGY Drug development Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation Phase I, II, III, IV Clinical Trials General Medical Practice Steps in cancer drug development Toxicology Pharmacology Biochemistry
  3. 3. ONCOLOGY Drug development Identification of candidate compounds: Natural products Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;387-388. Haskell CM. Cancer Treatment . 1995;35-36. Drug Type Source Antitumor antibiotic (daunorubicin, doxorubicin) Streptomyces fungus Vinca alkyloid (vincristine, vinblastine) Vinca rosea plant Taxane Yew tree Camptothecin (topotecan, CPT-11) Camptotheca accuminata tree Podophyllin (etoposide, teniposide) Podophyllum peltatum plant Bryostatin, dolastatin, halichondrin Marine organisms
  4. 4. ONCOLOGY Drug development <ul><li>Computer-aided construction of molecules </li></ul><ul><li>Mutant oncogenes (BCR-ABL) </li></ul><ul><li>Aberrant tumor suppressor genes (RB) </li></ul><ul><li>Protein kinases </li></ul><ul><li>Transcription activators </li></ul>Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology . 1997;385-394. Identification of candidate compounds: Molecular-targeted screening
  5. 5. ONCOLOGY Drug development Prostate IN VITRO HUMAN TUMOR CELL LINE PANELS Ovarian Melanoma CNS Breast Colon Lung Preclinical development followed by broad-based clinical trials In Vivo “tumor panel” human tumor xenograft studies Specific “disease-oriented” Phase I/II trials Targeted preclinical development “ Nonspecific” antitumor activity “Highly specific” antitumor activity Adapted from NCI drug screening strategy,1985. Screening for anticancer activity
  6. 6. ONCOLOGY Drug development <ul><li> Target level  Maximum tolerated dose  Spectrum of activity </li></ul><ul><li> Cellular level  Dose-limiting toxicities  Schedule dependency </li></ul><ul><li> Efficacy  Route of administration </li></ul><ul><li> Cross resistance </li></ul><ul><li> Combination therapies </li></ul>IN VITRO IN VIVO Preclinical evaluation of cytotoxic agents Mechanism of action Stage I Stage II
  7. 7. ONCOLOGY Drug development <ul><li>Preclinical studies in mice, rats, and dogs provide an important bridge from in vitro studies to clinical studies </li></ul><ul><li>Objectives </li></ul><ul><ul><li>Define major toxicities </li></ul></ul><ul><ul><li>Identify initial safe starting dose for clinical trials </li></ul></ul>Use of animal models in evaluation of cytotoxic agents
  8. 8. ONCOLOGY Drug development Clinical evaluation of cytotoxic agents Study Phase Objectives Patient Population Phase I  Identify maximum tolerated dose  Small (3-6 patients/dose level)  Define key toxicities  Various tumor types Phase II  Evaluate tumor response  Larger than Phase I (10-50  Determine whether drug patients/treatment group) warrants Phase III study  More uniform disease characteristics Phase III  Compare new treatment with  Larger than Phase II (100s of standard patients/treatment group)  Support marketing approval  Same tumor type  Broader patient pool Phase IV  Integrate clinical study experience  Very large cohorts (100s-1000s) into general clinical practice  Represent general patient  Monitor safety after approval population
  9. 9. ONCOLOGY Drug development <ul><li>Response rate </li></ul><ul><li>Survival </li></ul><ul><li>Disease-free survival </li></ul><ul><li>Time to disease progression </li></ul><ul><li>Duration of response </li></ul><ul><li>Quality of life </li></ul><ul><li>Pharmacoeconomics </li></ul>Clinical trials: Efficacy endpoints
  10. 10. ONCOLOGY Drug development Adapted from World Health Organization, 1980. Clinical endpoints: Complete remission Primary Tumor Nodes Metastases Disappearance of all clinical, radiologic and biologic signs of tumor Treatment
  11. 11. ONCOLOGY Drug development Treatment Decrease of the multiple of two tumor diameters by at least 50% Clinical endpoints: Partial remission Adapted from World Health Organization, 1980.
  12. 12. ONCOLOGY Drug development Increase of the multiple of two tumor diameters by at least 25% Clinical endpoints: Disease progression Adapted from World Health Organization, 1980. Treatment
  13. 13. ONCOLOGY Drug development <ul><li>Major toxicities </li></ul><ul><ul><li>Adverse effects </li></ul></ul><ul><ul><li>Need for dose/schedule modifications </li></ul></ul><ul><ul><li>Discontinuation of therapy during study </li></ul></ul>Clinical trials: Safety analyses
  14. 14. ONCOLOGY Drug development Summary of organization and reporting of clinical studies ETHICS COMMITTEE INVESTIGATOR PATIENTS PREPARATION OF DOCUMENTS CLINICAL SUPPLIES DATA ON ADVERSE EVENTS DATA PROCESSING WRITTEN ACCOUNTS MONITORING STUDY REPORT

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