1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug Development

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Steps in cancer drug development Drug development Steps in cancer drug development Identification of Candidate Compounds Screening Preclinical Evaluation Production and Formulation Phase I, II, III, IV Clinical Trials General Medical Practice ToxicologyPharmacologyBiochemistry

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Identification of candidate compounds: Natural products Drug development Identification of candidate compounds: Natural products Drug TypeSource Antitumor antibiotic (daunorubicin, doxorubicin)Streptomyces fungus Vinca alkyloid (vincristine, vinblastine)Vinca rosea plant TaxaneYew tree Camptothecin (topotecan, CPT-11)Camptotheca accuminata tree Podophyllin (etoposide, teniposide)Podophyllum peltatum plant Bryostatin, dolastatin, halichondrinMarine organisms

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Identification of candidate compounds: Molecular-targeted screening Drug development Identification of candidate compounds: Molecular-targeted screening Computer-aided construction of molecules Mutant oncogenes (BCR-ABL) Aberrant tumor suppressor genes (RB) Protein kinases Transcription activators

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Screening for anticancer activity Drug development Screening for anticancer activity Prostate IN VITRO HUMAN TUMOR CELL LINE PANELS OvarianMelanomaCNSBreastColonLung 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

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Preclinical evaluation of cytotoxic agents Drug development Preclinical evaluation of cytotoxic agents IN VITRO IN VIVO Mechanism of actionStage IStage II Target levelMaximum tolerated doseSpectrum of activity Cellular levelDose-limiting toxicitiesSchedule dependency EfficacyRoute of administration Cross resistance Combination therapies

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Use of animal models for evaluation of cytotoxic agents Drug development Use of animal models for evaluation of cytotoxic agents Preclinical studies in mice, rats, and dogs provide an important bridge from in vitro studies to clinical studies Objectives Define major toxicities Identify initial safe starting dose for clinical trials

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical evaluation of cytotoxic agents Drug development Clinical evaluation of cytotoxic agents Study Phase Objectives Patient Population Phase I Phase I Identify maximum tolerated dose Small (3-6 patients/dose level) Define key toxicities Various tumor types Phase II 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 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 Phase IV Integrate clinical study experience Very large cohorts (100s-1000s) into general clinical practice Represent general patient Monitor safety after approval population

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical trials: Efficacy endpoints Drug development Clinical trials: Efficacy endpoints Response rate Survival Disease-free survival Time to disease progression Duration of response Quality of life Pharmacoeconomics

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical endpoints: Complete remission Drug development Clinical endpoints: Complete remission

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical endpoints: Partial remission Drug development Clinical endpoints: Partial remission

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical endpoints: Disease Progression Drug development Clinical endpoints: Disease Progression

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Clinical trials: Safety analyses Drug development Clinical trials: Safety analyses Major toxicities Adverse effects Need for dose/schedule modifications Discontinuation of therapy during study

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Summary of organization and reporting of clinical studies Drug development Summary of organization and reporting of clinical studies ETHICSCOMMITTEEINVESTIGATORPATIENTS PREPARATIONOFDOCUMENTS CLINICALSUPPLIES DATA ON ADVERSEEVENTS DATAPROCESSING WRITTENACCOUNTS MONITORING STUDY REPORT