Pre-Clinical studies

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A detailed study on Pre-Clinical studies


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PRE-CLINICAL STUDIES: OBJECTTIVE, IMPORTANCE & STUDY DETAIL By Pratik A . Vora M.Pharm (Pharmaceutics) 2 nd semeseter (Batch A) Roll No. 02 25 th January, 2013 Guided by Lalit Lata Jha PARUL INSTITUTE OF PHARMACY 1


What is Pre-clinical Studies? Objective Importance Study detail GLP Role of F&D in Pre-clinical studies References 2 Content

What is Pre-Clinical Studies?: 

What is Pre-Clinical Studies? In drug development, pre-clinical studies OR non-clinical studies , is a stage of research that begins before clinical trials (testing in humans), and during which important testing and drug safety data is collected. The main goals of pre-clinical studies are to determine a product's ultimate safety profile . Products may include new medical devices, drugs , gene therapy solutions , etc. 3

Place of Pre-clinical Trials in whole drug development process:: 

Place of Pre-clinical Trials in whole drug development process: 4

Objective of Pre-Clinical Studies:: 

Objective of Pre-Clinical Studies: The purpose of pre-clinical study -- animal pharmacology/toxicology testing -- 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 . 5

Importance of Pre-Clinical Studies:: 

To determine the dose, toxic dose, pharmacological action, etc. It is the requirement of regulatory body for performing clinical trials. As ethical view point, it is necessary to check safety of drug on animals before starting to check on human being. To check the kinetic profile of drug & based on it, select the route of administration in human for clinical trials. 6 Importance of Pre-Clinical Studies:

Study detail of Pre-Clinical Studies:: 

After identifying a compound, it is tested on animals to expose the whole pharmacological profile. Experiments are generally performed on rodent like mouse, rat, guinea pig, hamster, rabbit. After successful result, experiments are performed on larger animals like cat, dog, monkey. As the evaluation progresses unfavorable compounds get rejected at each step. So, that only few out of thousands reach the stage when administration to man is considered. 7 Study detail of Pre-Clinical Studies:

Study detail of Pre-Clinical Studies:: 

In these studies, safety of compound in at least two animal species, mostly mouse/rat and dog by oral and parenteral routes. Various types of tests are performed. They are … 8 Study detail of Pre-Clinical Studies:

1. Screening Test:: 

1. Screening Test: These are simple and rapidly performed tests to indicate presence OR absence of a particular pharmacodynamic activity. For example, analgesic OR hypoglycemic activity. 2. Tests on isolated organs, bacterial cultures: These also are preliminary tests to detect specific activity, such as anti-histaminic, anti- secretory , vasodilator, antibacterial, etc. 9 Study detail of Pre-Clinical Studies:

3. Tests on animal models of human disease:: 

3. Tests on animal models of human disease: Animal models used such as kindled seizures in rats, genetically hypersensitive rats, experimental tuberculosis in mouse, etc. 4. General observational test: 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. 10 Study detail of Pre-Clinical Studies:

5. Confirmatory tests and analogous activities:: 

5. Confirmatory tests and analogous activities: Compounds found active are taken up for detailed study by more elaborate (Complex) tests which confirm and characterize the activity. Other related activities also measured, like antipyretic and anti-inflammatory activity in an analgesic. 11 Study detail of Pre-Clinical Studies:

6. Mechanism of action:: 

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. 7. Systemic pharmacology: Irrespective of the primary action of the drug, its effect on major organ systems such as nervous , cardio-vascular, respiratory , renal are worked out. 12 6. Mechanism of action: Study detail of Pre-Clinical Studies:

8. Quantitative test:: 

The dose-response relationship , maximal effects and comparative efficacy with existing drug is carried out. 9. Pharmacokinetics: The absorption, tissue distribution, metabolism, excretion, volume of distribution and half-life of drug are quantified. 13 8. Quantitative test: Study detail of Pre-Clinical Studies:

10. Toxicity test:: 

Acute toxicity: Single high doses are given to small groups of animals that are observed for overt (hidden) effects and mortality for 1-3 days . The dose which kills 50% animals is called as LD 50. Organ toxicity is examined by histopathology on all animals. 14 10. Toxicity test: Study detail of Pre-Clinical Studies:

10. Toxicity test:: 

Sub-acute toxicity: Repeated doses are given for 2-12 weeks depending on the duration of intended treatment in man. Doses are selected on LD 50 . Animals are examined for overt effects, food intake, body weight and organ toxicity. 15 Study detail of Pre-Clinical Studies: 10. Toxicity test:

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Chronic toxicity: The drug is given for 6-12 months and effects are studied as in sub-acute toxicity. This is generally undertaken with early clinical trials. Reproduction & Teratogenicity : Effects on ovulation, fertility and developing fetus are studied. 16 Study detail of Pre-Clinical Studies: 10. Toxicity test:

10. Toxicity test:: 

Mutagenicity : Ability of the drug to induce genetic damage is assessed in bacteria, mammalian cell cultures & in rodents. Carcinogenicity: Drug is given for long-term, even for the whole life of the animal & they are watched for development of tumors. 17 Study detail of Pre-Clinical Studies: 10. Toxicity test:

10. Toxicity test:: 

These whole tests are carried out under standardize procedure under “ Good Laboratory Practice ” ( GLP ). GLP specifically refers to a quality system of management controls for research laboratories and organizations to try to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of chemical (including pharmaceuticals) non-clinical safety tests; from physicochemical properties through acute to chronic toxicity tests. 18 Study detail of Pre-Clinical Studies: 10. Toxicity test:


GLP The original GLP regulatory mandate was promulgated in 1978 by US-FDA and published in the Federal Register 43 FR 59985-60020. GLP applies to non-clinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals) to man, animals and the environment. 19

Role of F&D department in Pre-Clinical Studies:: 

Role of F&D department in Pre-Clinical Studies: Let us see role of F&D department in the whole process for pre-clinical studies… F& D will receive ‘request form’ for formulation in the FORMULATION REQUEST SHEET from PCSED along with active bulk drug and analytical report / COA for the same. F& D will make a record of quantity of test substance received and utilised in TEST SUBSTANCE ACCOUNTIBILITY FORM. F& D will develop formulation at least three. They send the formulation to ADL for analysis with TEST REQUEST SHEET and respective placebo. 20

Role of F&D department in Pre-Clinical Studies:: 

If the assay value is + 5% of label claim, ADL will pass the formulation. Formulation for ACUTE ORAL TOXICITY STUDIES , stability for 4 hrs. shall be conducted. Accelerated stability studies should be conducted at 25 + 2ºC and 2-8ºC as per STABILTY STUDY PROTOCOL. For any other Toxicity Studies, limit is SUB ACUTE TOXICITY STUDIES : 8 days CHRONIC TOXICITY STUDIES : 30 days Once the formulation vehicle safety is established, document the composition in MASTER FORMULA CARD. 21 Role of F&D department in Pre-Clinical Studies:

Role of F&D department in Pre-Clinical Studies:: 

FORMULATION AND DEVELOPMENT OF ORAL & IV FORMULATION FOR PCSED TRIALS: ORAL: Information required: Solubility pKa Solution Stability Particle Size 22 Role of F&D department in Pre-Clinical Studies:

Role of F&D department in Pre-Clinical Studies:: 

IV: Based on the concentration required and solubility of the drug make a preliminary formulation. If solubility of the drug is not sufficient , try following: Try solubility at different pH. Try co-solvents like PEG 400, PG, Ethanol, Glycerine. Try surfactants like T-80, T-20, Cr RH 40, Cr El, etc. Try complexing agents like PVP K 30, Cyclodextrins , caffeine, etc. Formulate micro-emulsion. 23 Role of F&D department in Pre-Clinical Studies:

Role of F&D department in Pre-Clinical Studies:: 

ARCHIVING AND RETRIVAL OF RECORDS AT CENTRAL ARCHIEVE: Following items should be achieved: Equipment log books including use log books , calibration log books and maintenance log books . 24 Role of F&D department in Pre-Clinical Studies:

Role of F&D department in Pre-Clinical Studies:: 

RETAINING SAMPLES OF TEST SUBSTANCE WHICH HAVE BEEN USED FOR THE CONDUCTANCE OF REGULATORY TOXICITY STUDIES & SAFETY STUDIES: Quantity: 500mg-1.0 gm Properly label the container containing the test Substance: Name of the Product:_____________ Batch No.: ______________________ Mfg. Date: ______________________ Expiry Date: ____________________ Storage Condition: _______________ 25 Role of F&D department in Pre-Clinical Studies:

Various Forms…: 

Various Forms… Now, let us discuss various forms that have been mentioned earlier… FORMS.pdf So, in the last lets summarize whole PRE-CLINICAL STUDIES by a video… Pre-Clinical Studies.flv 26


27 REFERENCES BOOKS REVIWED: TRIPATHI K.D., Essentials of Medical Pharmacology, Sixth edition, Reprint 2009, Page No. 76-77 Small Animal Imaging: Basics and Practical Guide. Kiessling , Fabian ; Pichler , Bernd J. (Eds.). 1st Edition., 2011, Springer ISBN 978-3-642-12944-5 Willmann JK, van Bruggen N, Dinkelborg LM, Gambhir SS. Molecular imaging in drug development. Nat Rev Drug Discov 2008 Jul;7:591-607. Foster FS, Mehi J, Lukacs M, Hirson D, White C, Chaggares C, Needles A. A new 15-50 MHz array-based micro-ultrasound scanner for preclinical imaging. Ultrasound Med Biol. 2009 Oct;35(10):1700-8. Epub 3 August 2009. Koo V, Hamilton PW, Williamson K. Non-invasive in vivo imaging in small animal research. Cellular Oncology 2006;28:127-39. Schober O, Rahbar K, Riemann B. Multimodality molecular imaging – from target description to clinical studies. Eur J Nucl Med Mol Imaging 2009;36:302-14. Kovar , J.L., Johnson, M.A., Volcheck , W.M., Chen, J., and Simpson, M.A., Am. J. Pathol . 169, 1415 (2006).


28 REFERENCES WEBSITES REVIWED: pdf ppt Research ers/.../ Research %20Associates/Petro. ppt ppt

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ABBREVATIONS USED: ADL = Analytical and Diagnostics Laboratory PCSED = Pre-clinical Safety & Evaluation department COA= Certificate of Analysis 31