introduction to pre-clinical trials

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


2

Overview• Drug Development Review• Introduction• Review By FDA• Objectives• Importance• Goals• Types• Stages Of Preclinical Trials


3

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


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.


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.


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.


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.


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.


9

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


10

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


11

Types Of Preclinical Trials


12

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


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


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: 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


15

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


16

Stages of Preclinical Trials


17

Stages Of Preclinical DevelopmentLead Selection

and Optimisation

Drug Candidate

Confirmation

Preclinical Drug

Characterisation


18

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

19

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


20

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


Data From Previous Stages


21

Considerations for trialsSelection of

Relevant Animal Species

Age Physiological State

Manner of Delivery

Stability of Test Material


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

http://www.fda.gov/

http://www.medicinenet.com/

http://www.ncbi.nlm.nih.gov/pubmed/?term=Polson%20AG%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Fuji%20RN%5Bauth%5D

23


Thank You

introduction to pre-clinical trials

Health & Medicine