Transcript The Drug Development Process

The Drug Development Process
From Discovery to Market
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The Drug Development Process
Discovery
Periapproval
Development
Research
Preclinical
Phase I
Phase II
Phase III
10,000
250
100
70
30
IND
Filed
Phase IIIb Phase IV
20
NDA
Filed
Time to Market
15 Years
Life of Drug Patent
20 years
NDA
Approved
Objectives of Drug Discovery
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Will the drug fulfill an unmet medical need?
Does the drug work?
Does the drug fit the company portfolio?
Does the drug have obvious undesirable
properties?
• Can the drug be formulated easily?
• Can it be economically manufactured?
Sources of a New Drug
Random
Screening
Chemicals
Found in Humans
(Replacement
Therapy)
Synthetic
Novel
Chemical
New
Drug
Serendipity
Old Drug Found
to have a
New Use
Modification of
a Known Drug
Natural Chemical
Not Found in Humans
that has Activity
as a Drug
Drug Development: CMC
Chemistry, Manufacturing, and Controls
• Drug Substance: New Chemical Entity (NCE),
Test Article, Active Pharmaceutical Ingredient
(API)
• Drug Product: Formulated Drug, including
container and packaging
Drug Development: CMC
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Chemistry
Characterize drug
substance
Assay development
Impurity profile
Formulation
development
Stability of drug
substance and drug
product
Drug Development: CMC
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Manufacturing
Method of synthesis
(Expression system)
Purification
Formulation process
Packaging and
labeling
Storage
Drug Development: CMC
Controls
• Process control
• Quality control
• Quality assurance
Drug Development: CMC
• Complete physical and chemical
characterization
• Well-defined, controlled manufacturing process
• Compliance with cGMPs
(current Good Manufacturing Practices)
Drug Development: Preclinical
Discovery
Periapproval
Development
Research
Phase I
Phase II
Phase III
Phase IIIb Phase IV
Preclinical
IND
Filed
NDA
Filed
NDA
Approved
• Laboratory and animal testing
- Toxicology and pharmacokinetics
• 1 - 3 years
- Studies with various species and durations
• 250 compounds
Drug Development: Preclinical
Safety Pharmacology
In vitro and in vivo studies conducted to
determine whether this compound has any
effects on:
• Brain –
central nervous system
• Lungs –
respiratory system
• Heart –
cardiovascular system
Drug Development: Preclinical
Genetic Toxicology
In vitro and in vivo studies conducted to
determine whether this compound has the
potential to induce mutations and chromosomal
damage
• bacterial mutation
• cytogenetics
• mammalian gene mutation
Drug Development: Preclinical
•
•
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Animal Toxicity Studies
Single- and multiple-dose toxicity studies
Developmental and reproductive toxicology
(DART)
Carcinogenicity
Special toxicity studies/evaluations
– Immunotoxicity
– Immunogenicity
– Photosensitization
Drug Development: Preclinical
Acute Toxicology Studies
• Animals given a single
dose by the intended
route of exposure and
monitored for 14 days
• Clinical signs
• Information on overdose
effects
• Minimum and median
lethal dose
Repeat-Dose Toxicity Studies
• Study cumulative effects
• Extensive clinical
evaluation of test animals
–physical, neurologic,
and ophthalmic exams
–ECG evaluation
–Clinical and anatomic
pathology analyses
Drug Development: Preclinical
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Developmental and Reproductive Toxicology
(DART)
Effects on male and female fertility
Teratogenic potential (embryo-fetal toxicity)
Effect on peri- and post-natal development of
offspring, including maternal development
Supports inclusion of women
in clinical trials
Drug Development: Preclinical
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Carcinogenicity Studies
Test the potential to produce tumors in
animals
Lifetime exposure in rats and mice (2 years)
Large doses (MTD) are generally used
Effects may be due to exaggerated
pharmacodynamics
Not always needed in advance of safety and
efficacy trials
Drug Development: Preclinical
Exposure Assessment
• A few different terms: toxicokinetics,
pharmacokinetics, ADME, bioanalytical
• These all describe the science of determining
the levels of the drug that were absorbed into
the blood stream or tissues and how long it
stayed in the system.
• Key to determining dose levels and frequency
the drug can be taken (e.g., two times/day,
once/week, every 4 hours, etc.)
Drug Development: Preclinical
Definition “ADME”
•Absorption – does the
compound get into the body?
Plasma Concentration (ng/mL)
10000
1000
Male Rats
Female Rats
100
10
1
0.1
0
4
8
12
16
Time (hr)
20
24
•Distribution – where does it
go?
•Metabolism – what happens to
it when in the body?
•Excretion – how does it get
out?
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Filing an IND
•Information filed with
regulatory agency
providing the results from
the preclinical phase
testing
–Chemistry,
manufacturing, and
control information
–Pharmacology and
toxicology information
–Clinical information/
proposed clinical studies
to be conducted
• Purpose
– Required prior to conducting clinical
studies in humans
– Demonstrates the drug is safe
enough to administer to humans
– Represents the initiation of the first
phase of clinical development
•
i.e., Phase I or First in Human (FIH)
studies
• Duration and Success Rates
– 30 days for regulatory agency to
review
– 88% are approved
Drug Development: Clinical
Discovery
Research
Periapproval
Development
Preclinical
Phase II
Phase III
Phase IIIb Phase IV
Phase I
IND
Filed
• Is it safe?
• Determine dosage levels
• 20 - 100 healthy volunteers
• Up to 12 months
• 100 compounds
NDA
Filed
NDA
Approved
Drug Development: Clinical
– Initial introduction of drug in humans – Phase I
• 20-80 volunteers
• May be patients for life-threatening indications
– Single rising dose
• monitor clinical signs, laboratory tests, and PK
• escalate based on previous dose
– Multiple rising dose trial
• duration usually < 2 weeks
• monitor clinical signs, laboratory tests, and PK
70% move to Phase IIa
Drug Development: Clinical
Discovery
Research
Periapproval
Development
Preclinical
Phase III
Phase I
Phase IIIb Phase IV
Phase II
IND
Filed
• Is it safe and does it work?
• Refine dosage levels
• 50 - 500 patients
• Up to 2 years
• 70 compounds
NDA
Filed
NDA
Approved
Drug Development: Clinical
Proof of Concept (POC)
• Initial evaluation of safety and efficacy of drug
in patients
– 50 - 500 patients
• Dose range based on results of Phase I
studies
• Usually done in successive steps
– i.e., Phase IIa and Phase IIb
– May be done at multiple sites to enhance
recruiting
48% move to Phase III
Drug Development: Clinical
Discovery
Research
Periapproval
Development
Preclinical
Phase I
Phase IIIb Phase IV
Phase II
Phase III
IND
Filed
NDA
Filed
NDA
Approved
• Is it safe? Does it work? Any side effects?
• 1,000 - 3,000 patients
• Up to 4 years
• 30 compounds
Drug Development: Clinical
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Pivotal Studies
Statistical efficacy –
100s to 1,000s of patients
Reproducible - two
studies
Multiple centers
Placebo or other controls
Unbiased - blinded,
randomized
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Objectives of Phase III
Confirms therapeutic efficacy
Determines product labeling
Definitive efficacy in target
population
Characterize safety
– Patient variations
(genetics, life style)
– Extent of adverse effects
– Concomitant therapies
– Concomitant conditions
(liver impairment,
pregnancy, etc.)
Drug Development: Clinical
Discovery
Research
Periapproval
Development
Preclinical
Phase I
Phase II
Phase III
Phase IV
Phase IIIb
IND
Filed
NDA
Filed
NDA
Approved
• New Drug Application (NDA) is prepared and
submitted to regulatory authorities
• 2 months - 7 years
• Phase IIIb studies sometimes conducted
Drug Development: Market
• After NDA approval is
obtained, the
pharmaceutical
company will market
the drug.
• There are regulations
for product labeling,
naming, and
marketing (TV and
radio commercials
and print ads).
Drug Development: Market
Discovery
Research
Periapproval
Development
Preclinical
Phase I
Phase II
Phase III
Phase IIIb
Phase IV
IND
Filed
NDA
Filed
NDA
Approved
• "Real World" studies
• Validate clinical work and/or safety hypothesis
• Usually require large numbers of patients
• Up to 4 - 5 years
Drug Development: Market
Objectives of Phase IV - Postmarketing Studies
• Continue collecting safety/efficacy data after early market
approval
• Collect cost-effectiveness data
• Collect data for switch from prescription to
over-the-counter
Objectives of Phase IV - Line Extensions
• New clinical indications
• New dosage forms and formulation development
• Extend label (market support)
Drug Development: Market
Discovery
Periapproval
Development
Research
Preclinical
Phase I
Phase II
Phase III
10,000
250
100
70
30
IND
Filed
Phase IIIb Phase IV
20
NDA
Filed
NDA
Approved
The industry spends, on average,
approximately
$500 to $800 million
to bring a new medical therapy to market