Introduction to Pre-clinical Trials
- 1. 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 Introduction to Pre- Clinical Trials 2
- 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 Introduction to Pre- Clinical Trials 3
- 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. Introduction to Pre- Clinical Trials 4
- 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. Introduction to Pre- Clinical Trials 5
- 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. Introduction to Pre- Clinical Trials 6
- 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. Introduction to Pre- Clinical Trials 7
- 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. Introduction to Pre- Clinical Trials 8
- 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 9
- 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 Introduction to Pre- Clinical Trials 10
- 11. Introduction to Pre- Clinical Trials 11
- 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 Introduction to Pre- Clinical Trials 12
- 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 Introduction to Pre- Clinical Trials 13
- 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 Introduction to Pre- Clinical Trials 14
- 15. In Vivo Preclinical Trials (Contd.) Introduction to Pre- Clinical Trials 15 • 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
- 16. Introduction to Pre- Clinical Trials 16
- 17. Stages Of Preclinical Development Lead Selection and Optimisation Drug Candidate Confirmation Preclinical Drug Characterisation Introduction to Pre- Clinical Trials 17
- 18. Lead Selection and Optimisation • Structural Characterisation • Impurity Identification • Solubility Assessment • Prototype formulation • Stability Testing Essential Pharmaceuticals Introduction to Pre- Clinical Trials 18 • 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 Introduction to Pre- Clinical Trials 19
- 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 20 Data From Previous Stages
- 21. Considerations for trials Selection of Relevant Animal Species Age Physiological State Manner of Delivery Stability of Test Material Introduction to Pre- Clinical Trials 21
- 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 Introduction to Pre- Clinical Trials 22
- 23. Introduction to Pre-Clinical Trials 23 Thank You