Professional Documents
Culture Documents
I. Background
II. The R&D Landscape
III. Innovation and Transformation
IV. The Preclinical Development Process
V. Case Study: A Novel Antidepressant
VI. Ethical Issues: Money, Data, & Politics
Disclaimer
Hoffman
Osterloh
I. Background
US FDA
250 Compounds
Phase I
20-100
Volunteers
Phase III
1000-5000
Volunteers
5 Compounds
NDA Submitted
10,000
Compounds
FDA
Review
Clinical Trials
Pre-Clinical
IND Submitted
Drug
Discovery
Large Scale
Manufacturing
/ Phase IV
1 FDA
Approved
Drug
Phase II
100-500
Volunteers
5 years
1.5 years
6 years
2 years
2 years
Hu et al (2007)
Fluvoxamine
1987
Fluoxetine
(Prozac; Lilly)
1992
Sertraline
1993
Venlafaxine
1996
Buproprion
2002
Escitalopram
2004
Duloxetine
2008
Desvenlafaxine
2011
Vilazidone
SSRI
Preclinical Development
Drug Candidate
Confirmation
Preclinical Drug
Characterization
ADME Profiling: How can it be delivered and what does the body do?
Screening Efficacy
In vitro models
In vivo models
Other
Structural Characterization
Impurity Identification
Solubility assessment
Prototype formulation
Stability testing
Early ADME
In silico profiling
Develop simple
analytical method
Measure membrane
permeability
Plasma Stability
Early Toxicology
Preliminary CMC
(Chemistry,
Manufacture and
Control)
Formulation for
GLP Toxicology
Stability testing
of active
ingredient
Detailed
physicochemical
characterization
Impurity
analysis
Benchmark in
vivo Models
In vivo models
Validated
models
Models in other
disease areas
ADME Profiling
Preliminary
Toxicology
Optimized
analytical
method
development
Basic pharmacokinetics (PK)
& Oral
Bioavailability
Determine
metabolism of
drug
Maximum
tolerated dose
(MTD)
Repeat Dose
(non-GLP)
Preliminary
Cardiovascular
Safety
Pharmacology
Detailed Preclinical
CMC
ICH Stability
Testing
ICH impurity
analysis
Develop prototype
clinical formulation
Comprehensive
ADME
GLP Toxicology
Package
analytical method
development
Comprehensive
Pharmacokinetics
GLP TK
Comprehensive
identification of
metabolites
acute study
subchronic repeat
dose study
Genotoxicity
Battery
Safety
Pharmacology
Anhedonia
Blunted Affect
Disturbed Sleep
Weight Gain/Weight Loss
Compromised Social Interactions
The Scream
Hippocampus
and Amygdala
Anterior &
Rostral
Cingulate
Cortex
Insular Cortex
Hypothalamic-Pituitary-Adrenal Axis
Biological Sciences
Hypothalamic-Pituitary-Adrenal Axis
Key Considerations
Regulatory Peptides
CRF
AVP
Feedback Regulation
Glucocorticoids
Biorhythm Disturbance
Sleep
Temperature
Cardiac
HPA axis
Biological Sciences
V. Ethics
Neurontin
PFIZER LOSES A ROUND OVER MARKETING OF NEURONTIN
By BLOOMBERG NEWS
A judge in Boston upheld a jury decision that Pfizer illegally promoted Neurontin for
unapproved uses. Pfizer said it would appeal. January 29, 2011
EXPERTS CONCLUDE PFIZER MANIPULATED STUDIES
By STEPHANIE SAUL
The drug maker manipulated the publication of studies to bolster use of its epilepsy drug
Neurontin, according to expert witnesses in a lawsuit against the company. Oct 8, 2008
http://www.youtube.com/watch?v=pPZn9mRQlq4
Hoffman
Osterhloh