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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