Professional Documents
Culture Documents
DR G A WAGHMARE
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Contents
1. Introduction
3. Regulatory Guidelines.
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• To bring a new drug to market requires a good
market.
12 years. 21/8/11 4
A Pyramid of Uncertainty
• Time:- It takes 12 years on average for an
experimental drug to travel from lab to medicine
chest.
• Discovery 5,000-10,000
• Preclinical testing 250
• Phase I 5
• Phase II 1
• Phase III 1
• FDA review & approval 1
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Attrition rate of overall drug development
&
Average cost of drug development
Chemical
Labs
10,000 Pharmacology
compounds Toxicology
1000 >$ Clinical
250
Decision compounds millio Trials
Filter n
Decision 10
NDA submission Filter compounds
IND submission
1 Decision
compound Filter
Decision
Filter > $ 250
million
US – FDA
Europe – EMEA
UK – MHRA
Japan – MHLW
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4.Steps in new drug development
1. Target Identification
2. Target validation
3. Lead Identification
4. Lead Optimization
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Target Identification and Validation :
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Lead identification :
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Characteristics of Ideal Drug
• High Potency Candidate
• High Selectivity
• Good oral
Bioavailability
• Low or no
interaction with
CYP450
• Less or minimal
adverse effects
• Good therapeutic
index
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C. Screening
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Pharmacological screening of candidate
molecules
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Pharmacological screening of
candidate molecules
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Through this process one can rapidly identify active
compounds, antibodies or genes which modulate
a particular biomolecular pathway.
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D. Pre-clinical Studies
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• Pharmacologic studies :
– Carried out in experimental animals using in vivo or in vitro
techniques.
– These studies bring out specific biological activities,
mechanism of action, PK, effective dose range of the test
compounds.
• Toxicity studies :
– Detailed toxicity studies are conducted on compounds
tested positive pharmacologically.
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Preclinical safety and toxicity testing
Goals:
• DRUG +
Additive: filler, lubricant, coating, stabiliser, colour,
binder, disintegrator
Dosage form: capsule, tablet, injection, other?
Manipulate duration/profile: e.g. sustained release
Bioequivalence
Bioavailability
Ease of use
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F. IND application
• IND application is a result of successful preclinical
development program.
• Contents :
– Animal pharmacological & toxicology studies.
– Manufacturing information.
– Clinical protocols and investigator information.
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Sponsor/FDA Meetings ( Pre-IND)
• Prior to clinical studies, the sponsor needs
evidence that the compound is biologically
active, and both sponsor and the FDA needs
data showing that the drug is reasonably safe
for initial administration to humans.
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29
G. Clinical studies
– Phase I
– Phase II
– Phase III
– Phase IV
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Phase I trials
– Human / Clinical Pharmacology Trials
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Objectives
• Safety & tolerability
• Pharmacokinetics
• Pharmacodynamics
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Players In Phase I Trials
Participants (20-80)
• Healthy volunteer subjects
• Patients
Place
• Special testing facilities
• Monitored closely
Physician
• Trained investigator
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Phase II trials
• Therapeutic exploratory trials
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Objectives
• Effectiveness of the drug
• Common short term side effects and risks
with I.N.D.
• Determine doses and regimens for phase III
trials
• PK, PD, safety
Additional objectives
• Therapeutic regimens
• Target populations for further studies in phase III
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Players In Phase II Trials
Participants (50-300)
• Patients
Place
• Specialized hospital units
• Closely monitored
Physician
• Trained investigators
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Sponsor/FDA Meeting (End of Phase
2)
• One month prior to the “end of the Phase 2”, the sponsor
should submit the background information and protocols
for phase 3 studies.
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Phase III trials
• They are initiated when the data generated
shows evidence of efficacy.
• Patients (300-3,000)
• Patients-250-1000+
• SITE
Multi-speciality hospital with adequate
patient attendance and laboratory facilities
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Clinical Trial Design
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H .Official license /Marketing
NDA /MAA
• New drug application (NDA) is a vehicle through which
sponsors formally propose that FDA approve it - new
pharmaceutical - for sale in United States.
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44
Phase IV
• This constitutes a vigilant post-marketing
surveillance to monitor safety of new drug.
• Pharmacoeconomics
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Conduct of Phase IV trial
• Players
Principal investigators-General practitioners and
Specialists
Participants patients-2000-10000+
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From Laboratory to Clinics Phase IV, PMS
Observational
A Phased Journey studies
Phase III b
III a
N P
D R
A O
Phase II a,b D
S
U
C
U
T
Phase I B L
M A
I U
S N
C
S H
I
Preclinical IND SUBMISSION21/8/11 48
5. Timelines of Patent
50
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• Drug discovery:
Ideas Drug candidates & biochemical tools
• Drug development:
Drug candidates Drugs
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Advances in drug development.
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Phase 0 microdosing
A new approach to obtain human pharmacokinetic information
before the usual expensive phase I safety program is conducted is
the phase 0 microdosing.
Thus, microdose studies use minute quantities of drug and are not
intended to produce any pharmacologic effect, when administered
to humans, and, therefore, may not cause any adverse events also,
but may produce useful pharmacokinetic information and help in
further development of the compound.
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• 1/100th of dose anticipated to produce a pharmacological
effect
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Microdosi
ng
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