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Drug Development Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Steps in cancer drug development Identification of Candidate Compounds Screening Preclinical Evaluation Production and Formulation Toxicology Pharmacology Biochemistry Phase I, II, III, IV Clinical Trials Clinical Division of Oncology Department of Medicine I General Medical Practice Medical University of Vienna, Austria Drug development Identification of candidate compounds: Natural products 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 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 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 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Screening for anticancer activity IN VITRO HUMAN TUMOR CELL LINE PANELS Lung Colon Breast “Nonspecific” antitumor activity CNS Melanoma Ovarian Prostate “Highly specific” antitumor activity In Vivo “tumor panel” human tumor xenograft studies Targeted preclinical development Preclinical development followed by broad-based clinical trials Specific “disease-oriented” Phase I/II trials Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Preclinical evaluation of cytotoxic agents IN VITRO IN VIVO Mechanism of action Stage I Stage II Target level Maximum tolerated dose Spectrum of activity Cellular level Dose-limiting toxicities Schedule dependency Efficacy Route of administration Cross resistance Combination therapies Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria 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 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical evaluation of cytotoxic agents Study Phase Objectives Patient Population Phase I Identify maximum tolerated dose Define key toxicities Small (3-6 patients/dose level) Various tumor types Phase II Evaluate tumor response Determine whether drug warrants Phase III study Larger than Phase I (10-50 patients/treatment group) More uniform disease characteristics Phase III Compare new treatment with standard Support marketing approval Larger than Phase II (100s of patients/treatment group) Same tumor type Broader patient pool Phase IV Integrate clinical study experience into general clinical practice Monitor safety after approval Very large cohorts (100s-1000s) Represent general patient population Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical trials: Efficacy endpoints Response rate Survival Disease-free survival Time to disease progression Duration of response Quality of life Pharmacoeconomics Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical endpoints: Complete remission Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical endpoints: Partial remission Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical endpoints: Disease Progression Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Clinical trials: Safety analyses Major toxicities Adverse effects Need for dose/schedule modifications Discontinuation of therapy during study Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Drug development Summary of organization and reporting of clinical studies PREPARATION OF DOCUMENTS CLINICAL SUPPLIES ETHICS COMMITTEE MONITORING WRITTEN ACCOUNTS INVESTIGATOR PATIENTS DATA PROCESSING DATA ON ADVERSE EVENTS STUDY REPORT Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria