introduction to pre-clinical trials
TRANSCRIPT
Introduction to Pre-Clinical Trials
By- Gargi Nanda (Exam No. 1)Kirti Jadhav (Exam No. 2)M.Pharm- 1 (PT)Guided By- Madam Krutika Sawant
Introduction to Pre-Clinical Trials
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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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Drug Development Review
Post Market Safety MonitoringSupplemental 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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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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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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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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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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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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Importance of Preclinical TrialsDetermination 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 administrationImportance
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Goals Of Preclinical StudiesIdentify 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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Types Of Preclinical Trials
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Types of TrialsIn Vitro Preclinical
Trials
Pharmacokinetics
Pharmacodynamics
In Vivo Preclinical Trials
ScreeningIsolated Organ
Bacteria CultureAnimal Models
General ObservationConfirmatory
Mechanism of ActionSystemic Pharmacology
Quantitative TestToxicity Tests
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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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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: Antipyretics
Isolated Organs
•Study of any activity using bacterial cultures•Eg: Antibiotics
Bacterial 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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In Vivo Preclinical Trials (Contd.)
•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 ToxicityMutagenicity•TeratogenicityOncogenicity
Toxicity Tests
•Compounds found active are taken up for detailed study by more elaborate (Complex) tests which confirm and characterize the activity.
Confirmatory Tests
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Stages of Preclinical Trials
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Stages Of Preclinical DevelopmentLead Selection
and Optimisation
Drug Candidate
Confirmation
Preclinical Drug
Characterisation
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Lead Selection and Optimisation
• Structural Characterisation
• Impurity Identification
• Solubility Assessment
• Prototype formulation
• Stability Testing
Essential Pharmaceutica
ls
•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 cytotoxicityEarly
Toxicology
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Drug Candidate ConfirmationPreliminary 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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Preclinical Drug CharacteristicsDetailed 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
CMCComprehensi
ve ADMEGLP
ToxicologyPresentation to Pharma
Introduction to Pre-Clinical Trials
Data From Previous Stages
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Considerations for trialsSelection of
Relevant Animal Species
Age Physiological State
Manner of Delivery
Stability of Test Material
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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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Introduction to Pre-Clinical Trials
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