2. Overview
• Drug Development Review
• Introduction
• Review By FDA
• Objectives
• Importance
• Goals
• Types
• Stages Of Preclinical Trials
Introduction to Pre-
Clinical Trials
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3. Drug Development Review
Post Market Safety Monitoring
Supplemental Application IND Application Manufacturer Inspection Drug Advertising Reporting Problems Active Surveillance
FDA Approval
NDA FDA Review FDA Approval
Clinical studies
Phase I Phase II Phase III
Preclinical Studies
In-Vitro In-Vivo
Discovery and Development
Discovery of new treatment and development of new formula
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Clinical Trials
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4. Introduction
• Pre-Clinical Trials is a study to test a drug, a procedure, or another
medical treatment in animals.
• In drug development, pre-clinical development, also
named preclinical studies and nonclinical studies, is a stage of
research that begins before clinical trials (testing in humans) can
begin, and during which important feasibility, iterative testing and
drug safety data is collected.
• It also means in vivo or in vitro experiments in which test articles
are studied prospectively in test systems under laboratory
conditions to determine their safety.
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Clinical Trials
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5. Introduction (Contd.)
• We assume that
▫ In vitro assays predict in vivo effects
▫ The effects of chemicals in laboratory animals apply to humans
▫ The use of high doses in animals is valid for predicting possible toxicity
in humans.
• These assumptions are broadly true, but despite this, we cannot be
certain that a chemical will show no toxic effects in humans.
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Clinical Trials
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6. Preclinical Review by FDA
• Under FDA requirements, a sponsor must first submit data showing
that the drug is reasonably safe for use in initial, small-scale clinical
studies. Depending on whether the compound has been studied or
marketed previously, the sponsor may have several options for
fulfilling this requirement:
▫ Compiling existing nonclinical data from past in vitro laboratory or
animal studies on the compound
▫ Compiling data from previous clinical testing or marketing of the drug
▫ Undertaking new preclinical studies designed to provide the evidence
necessary to support the safety of administering the compound to
humans.
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Clinical Trials
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7. Preclinical Review By FDA (Contd.)
• At the preclinical stage, the FDA will generally ask,
▫ Develop a pharmacological profile of the drug
▫ Determine the acute toxicity of the drug in at least two species of animals
▫ Conduct short-term toxicity studies ranging from 2 weeks to 3 months,
depending on the proposed duration of use of the substance in the
proposed clinical studies.
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Clinical Trials
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8. Objectives of Preclinical Trial
• Objective is to develop adequate data to decide that it is reasonably
safe to proceed with human trials of the drug, means, a laboratory
test of a new drug or a new medical device, usually done on animal
subjects, to see if the treatment really works and if it is safe to test
on humans.
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Clinical Trials
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9. Importance of Preclinical Trials
Determination of dose, toxic
dose, pharmacological action,
etc.
Requirement of regulatory body
Necessary to check safety of
drug on animals before starting
to check on human being.
Check for kinetic profile of drug
and on this basis, selection of
route of administration
Importance
Introduction to Pre-
Clinical Trials
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10. Goals Of Preclinical Studies
Identify initial safe dose and dose escalation
schemes in humans
Identify target organs for toxicity
Study of such toxicity whether reversible
Identify safety parameters for clinical
monitoring
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Clinical Trials
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12. Types of Trials
In Vitro Preclinical
Trials
Pharmacokinetics
Pharmacodynamics
In Vivo Preclinical Trials
Screening
Isolated Organ
Bacteria Culture
Animal Models
General Observation
Confirmatory
Mechanism of Action
Systemic Pharmacology
Quantitative Test
Toxicity Tests
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Clinical Trials
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13. In Vitro Preclinical Trials
• Needed for better characterisation by providing evidence for the
desired biological effect of a drug.
• Providing insight into potential toxicities to establish a human starting
dose
Pharmacodynamic Studies
• The absorption, tissue distribution, metabolism, excretion, volume of
distribution and half-life of drug are quantified.
Pharmacokinetic Studies
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Clinical Trials
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14. In Vivo Preclinical Trials
• Simple and rapidly performed tests to indicate presence or absence of a
particular activity.Screening
• Study of activity on isolated organs
• Eg: AntipyreticsIsolated Organs
• Study of any activity using bacterial cultures
• Eg: AntibioticsBacterial Cultures
• Animal models used
• Eg. Kindled seizures in rats, genetically hypersensitive rats, experimental
tuberculosis in mouse
Animal Models
• Drug is injected in tripling doses to small groups of mice which are observed
for overt (hidden) effects.
• Preliminary clues are drawn from the profile of effect observed.
General Observations
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Clinical Trials
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15. In Vivo Preclinical Trials (Contd.)
Introduction to Pre-
Clinical Trials
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• Attempts are made to find out the mechanism of action.
• E.g. whether an anti-hypertensive is an α blocker/ β blocker/ ACE inhibitor/
calcium channel blocker, etc.
Mechanism of Action
• Irrespective of the primary action of the drug, its effect on major organ systems
such as nervous, cardio-vascular, respiratory, renal are worked out.Systemic Pharmacology
• The dose-response relationship, maximal effects and comparative efficacy with
existing drug is carried out
Quantitative Tests
• Chronic Toxicity Mutagenicity
• Teratogenicity OncogenicityToxicity Tests
• Compounds found active are taken up for detailed study by more
elaborate (Complex) tests which confirm and characterize the activity.Confirmatory Tests
17. Stages Of Preclinical Development
Lead Selection
and
Optimisation
Drug Candidate
Confirmation
Preclinical Drug
Characterisation
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Clinical Trials
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18. Lead Selection and Optimisation
• Structural
Characterisation
• Impurity
Identification
• Solubility
Assessment
• Prototype
formulation
• Stability Testing
Essential
Pharmaceuticals
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Clinical Trials
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• In vitro models
• In vivo models
• Other models
Screening
Efficacy
• In silico profiling
• Plasma Stability
• Membrane Permeability
• Develop analytical method
Early
ADME
• Off screen target
• In vitro cytotoxicity
Early
Toxicology
19. Drug Candidate Confirmation
Preliminary Chemistry,
Manufacture, Control
Formulation for GLP
Toxicology
Stability Testing of API
Physicochemical
Characterisation
Impurity Analysis
In Vivo Models
Validated Models
Models in other disease
areas
ADME Profiling
Analytical method
Development
P’cokinetics and Oral
Bioavailability
Drug Metabolism
Preliminary Toxicology
Maximum Tolerated Dose
Repeat Dose
Cardiovascular Safety
Pharmacology
Data from Lead Selection and Optimisation
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Clinical Trials
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20. Preclinical Drug Characteristics
Detailed Preclinical CMC
• ICH Stability Testing
• ICH Impurity Analysis
• Prototype Formulation
Comprehensive ADME
• Analytical Method Development
• P’cokinetics
• Identification of Metabolites
GLP Toxicology Package
• Acute Study
• Subchronic Repeat Dose Study
• Genotoxicity Study
• Safety Pharmacology
Detailed
Preclinical CMC
Comprehensive
ADME GLP Toxicology
Presentation to
Pharma
Introduction to Pre-
Clinical Trials
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Data From Previous Stages
21. Considerations for trials
Selection of
Relevant
Animal Species
Age
Physiological
State
Manner of
Delivery
Stability of Test
Material
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Clinical Trials
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22. Reference
• www.fda.gov
• www.medicinenet.com
• ICH Guidelines
• BRITISH JOURNAL OF PHARMACOLOGY The successes
and limitations of preclinical studies in predicting the
pharmacodynamics and safety of cell-surface-
targeted biological agents in patients; Andrew G
Polson and Reina N Fuji
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Clinical Trials
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