ONCOLOGYONCOLOGYDrug DevelopmentDrug Development
Fadi Sami Farhat, MDFadi Sami Farhat, MDHematology Oncology
Identify Candidate CompoundsIdentify Candidate Compounds
ScreeningScreening
Preclinical EvaluationPreclinical Evaluation
Production and FormulationProduction and Formulation
Phase I, II, III, IV Clinical TrialsPhase I, II, III, IV Clinical Trials
General Medical PracticeGeneral Medical Practice
ToxicologyToxicology PharmacologyPharmacology BiochemistryBiochemistry
ONCOLOGYONCOLOGYDrug developmentDrug developmentSteps in cancer drug developmentSteps in cancer drug development
ONCOLOGYONCOLOGYDrug developmentDrug developmentIdentification of candidate compounds: Natural productsIdentification of candidate compounds: Natural products
Drug TypeDrug Type SourceSource
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
Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.Haskell CM. Cancer Treatment. 1995;35-36.
Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.
Identification of candidate compounds: Molecular-targeted screeningIdentification of candidate compounds: Molecular-targeted screening
ONCOLOGYONCOLOGYDrug developmentDrug development
Computer-aided construction of molecules
Mutant oncogenes (BCR-ABL)
Aberrant tumor suppressor genes (RB)
Protein kinases
Transcription activators
ProstateProstate
IN VITROIN VITRO HUMAN TUMOR CELL LINE PANELS HUMAN TUMOR CELL LINE PANELS
OvarianOvarianMelanomaMelanomaCNSCNSBreastBreastColonColonLungLung
Preclinical developmentPreclinical developmentfollowed by broad-based clinical trialsfollowed by broad-based clinical trials
In VivoIn Vivo “tumor panel” “tumor panel”human tumor xenograft studieshuman tumor xenograft studies
Specific “disease-oriented”Specific “disease-oriented”Phase I/II trialsPhase I/II trials
Targeted preclinical developmentTargeted preclinical development
““Nonspecific” antitumor activityNonspecific” antitumor activity “Highly specific” antitumor activity“Highly specific” antitumor activity
Adapted from NCI drug screening strategy,1985.
ONCOLOGYONCOLOGYDrug developmentDrug developmentScreening for anticancer activityScreening for anticancer activity
ONCOLOGYONCOLOGYDrug developmentDrug development
IN VITROIN VITRO IN VIVOIN VIVO
Preclinical evaluation of cytotoxic agentsPreclinical evaluation of cytotoxic agents
Mechanism of actionMechanism of action Stage IStage I Stage IIStage II
Target level Maximum tolerated dose Spectrum of activity
Cellular level Dose-limiting toxicities Schedule dependency
Efficacy Route of administration
Cross resistance
Combination therapies
ONCOLOGYONCOLOGYDrug developmentDrug development
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
Use of animal models in evaluation of cytotoxic agentsUse of animal models in evaluation of cytotoxic agents
Study PhaseStudy Phase ObjectivesObjectives Patient PopulationPatient Population
Phase IPhase I Identify maximum tolerated dose Small (3-6 patients/dose level)
Define key toxicities Various tumor types
Phase IIPhase 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 IIIPhase 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 IVPhase IV Integrate clinical study experience Very large cohorts (100s-1000s)
into general clinical practice Represent general patient
Monitor safety after approval population
ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical evaluation of cytotoxic agentsClinical evaluation of cytotoxic agents
ONCOLOGYONCOLOGYDrug developmentDrug development
Response rate
Survival
Disease-free survival
Time to disease progression
Duration of response
Quality of life
Pharmacoeconomics
Clinical trials: Efficacy endpointsClinical trials: Efficacy endpoints
Adapted from World Health Organization, 1980.
Clinical endpoints: Complete remissionClinical endpoints: Complete remission
ONCOLOGYONCOLOGYDrug developmentDrug development
PrimaryPrimaryTumorTumor
NodesNodes
MetastasesMetastases
Disappearance of all clinical,Disappearance of all clinical,radiologic and biologicradiologic and biologic
signs of tumorsigns of tumor
TreatmentTreatment
TreatmentTreatment
Decrease of the multiple of twoDecrease of the multiple of twotumor diameters by at least 50%tumor diameters by at least 50%
ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical endpoints: Partial remissionClinical endpoints: Partial remission
Adapted from World Health Organization, 1980.
Increase of the multiple of twoIncrease of the multiple of twotumor diameters by at least 25%tumor diameters by at least 25%
ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical endpoints: Disease progressionClinical endpoints: Disease progression
Adapted from World Health Organization, 1980.
TreatmentTreatment
ONCOLOGYONCOLOGYDrug developmentDrug development
Major toxicities
– Adverse effects
– Need for dose/schedule modifications
– Discontinuation of therapy during study
Clinical trials: Safety analysesClinical trials: Safety analyses
ETHICSETHICSCOMMITTEECOMMITTEE
INVESTIGATORINVESTIGATOR
PATIENTSPATIENTS
PREPARATIONPREPARATIONOFOF
DOCUMENTSDOCUMENTS
CLINICALCLINICALSUPPLIESSUPPLIES
DATA ONDATA ONADVERSEADVERSEEVENTSEVENTS
DATADATAPROCESSINGPROCESSING
WRITTENWRITTENACCOUNTSACCOUNTS
MONITORINGMONITORING
STUDY REPORTSTUDY REPORT
ONCOLOGYONCOLOGYDrug developmentDrug developmentSummary of organization and reporting of clinical studiesSummary of organization and reporting of clinical studies