The document discusses the drug discovery and development process. It begins by outlining the key steps from lead identification to establishing proof of concept, including medicinal chemistry, biological screening, and ADME-PK analysis. It then provides an overview of the drug development phases, noting they can take 10 years on average and involve screening thousands of compounds. The document details each phase of clinical trials and highlights the low success rates. It concludes by defining some key terms in the drug discovery process and noting the reality that the majority of programs fail due to lack of efficacy, toxicity, or pharmacokinetic issues.

1. The Drug Discovery and
Development Process
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2. Lead To Proof Of Concept
• Technologies & Solutions for Selecting Best Clinical
Candidate
– Medicinal Chemistry
– Biological Screening Assays
– High Throughput Purification & Analysis
– ADME-PK
– Data Management
• Technologies and Solutions for Establishing POC
– Process Chemistry & Development
– Analytical Method Development & Validation
– Bio-analytical
– Regulatory & Clinical Affairs
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3. Overview of the Drug
Development Process
• Statistics related to Research and
Development
• Process of Drug Development
• Phases Involved in Drug Development
• Success vs Failures – What Accounts for
Each?
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4. What are the Characteristics of
Pharmaceutical R&D?
• Based on commercialization of biomedical
research discoveries
• Innovation is critical to the process
• Specialized research is essential and
development cycles are very long
• Resulting drug candidates/products must:
– be treatment breakthroughs
– have better profiles than existing treatments
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5. Basic Statistics for
Pharmaceutical Industry
• Pharmaceutical R&D is high-risk and also very high cost
• Average cost to discover and develop one compound =
$0.8-1Billion
• Takes on average 10 years to go from shelf to pharmacy
shelf
• Need to screen 5,000 – 10,000 compounds to generate
an approved drug
• About 3/10 drug products make profits that match or
exceed R&D costs
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6. R&D Success Rates by Development Stage
Discovery (2-10 yrs) Compound Success Rates by Stage
5,000 – 10,000 screened
Preclinical Testing
Lab & animal testing 250 Enter
Pre-clinical Testing
Phase I
20-80 healthy volunteers
for safety & dosage
5 Enter Clinical Testing
Phase II
100-300 patient volunteers used to
1 Approved by FDA
for efficacy & side effects
Phase III
1,000-5,000 patient volunteers used to
monitor efficacy & side effects adverse
reactions to long-term use
FDA Review/Approval
Additional Post-marketing testing
Years
0 2 4 6 8 10 12 14 16
Source: PhRMA based on data from Center for the Study of Drug Development, Tufts University

7. The Drug Development Process
Process Development
Screening
Lead Formulation/Stability
Identified
Preclinical File Post
Drug IND/CTC CTC/ File Filing
Sourcing Workup IND Phase I Phase II Phase III WMA Activities
A
Patent process P
Metabolism
R
O
V
Toxicology A
L
Preclinical Registration Post-submission
Discovery Screening Development Preparation Activity
Up to 15 years

8. Pharmaceutical R&D Phases
• Basic Drug Discovery Res. (6 mths – 16 yrs)
– Evidence for role of enzyme, receptor, gene or
pathway in disease
– Drug target selection and validation
– Compounds screening – natural & synthetics
– Rational drug design/ molecular modeling
– Hit-to-lead, lead optimization and selection
• Safety assessment process begins

9. Clinical Development: Phase I
• Approximately 10-40 patients – up to 1 yr
• Safety and tolerability – healthy volunteers
• Evidence of activity in some areas
• Produce a clinical pharmacology package
– Bioequivalence studies
– Drug interactions
– Different populations (pediatrics, elderly,
kidney/liver dysfunction)

10. Clinical Development: Phase II
• Phase IIA
– 10-100 patients with target disease
– Clinical/efficacy “Proof of Concept”
– Normally lasts 9-12 months
• Phase IIB
– 100 – 200 patients
– Dose ranging studies
– Set minimum effective dose
– Essential to design Phase III
– Normally lasts 9-12 months

11. Clinical Development: Phase III
• 1,000 – 4,000 patients
• Also called “Pivotal Studies”
• To Demonstrate Safety & Efficacy
• Randomized, well-controlled, blinded
• Patient outcomes included in the
endpoints
• Timing: 2-4 years

12. Clinical Development: Phase IV
• Typically specified by the regulatory
agencies – safety is the usual reason
• Normally required/condition for approval
• 10 – 1,000 patients
• Could require outcomes/endpoint studies
• Phase V Clinical Development
– New claims, new dosage forms, market
support, comparisons to competitors, etc.

13. New Molecular Entities (%) Entering Each
Phase of Clinical Trials
The price of innovation: New estimates of drug development costs
Journal of Health Economics, Vol 22 (2003), pp 151-185.

14. Typical Drug Discovery Process
“Pre-clinical
“Hit” “Lead” candidate”
Active-to-Hit Hit-to-Lead Lead Optimization
HTS (AtH) (HtL) (LO)
Compound Initial SAR, Iterative design
Hit resynthesis
acquisition near neighbor synthesis and synthesis
Chemistry Data analysis and mining Mol modeling, SAR dev
Biology Screening
Biochemical “mechanism of action” screens
In vivo efficacy screens
Acute tox Chronic tox
DMPK Purity, identity determ Physchem prop screens
ADME screens (in vitro perm, metab, safety)
In vivo DMPK

15. Some Key Definitions
• “Hit” = compound(s) which have demonstrated
reproducible, dose-responsive activity in a primary
biological assay
• “Lead” = compound(s) which have been shown to exhibit
properties (activity, selectivity, ADME, etc.) perceived to
optimizable through iterative cycles of medicinal
chemistry and biological evaluation
• “Pre-clinical candidate” = compound which has in vivo
efficacy, in vivo PK, selectivity and toxicological
properties consistent with a pre-defined Target Product
Profile

16. Failure: The Reality of Drug Discovery
Historically, the majority of Hit-to-Lead and
Lead Optimization programs fail to deliver
a pre-clinical candidate due to:
– Lack of efficacy (in animal models)
– Unexpected toxicity
– Poor pharmacokinetics
If you must fail…
“Fail early, fail cheap”

17. THANK YOU
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18. June 7, 2012 Sokoine University of Agriculture