The document discusses the steps involved in preclinical trials for new drug development. Preclinical trials involve laboratory and animal testing to evaluate safety and efficacy before human testing. Key steps include: identifying a drug target and developing a bioassay; screening the drug in the bioassay; establishing effective and toxic doses; filing for Investigational New Drug approval with the FDA; and conducting various studies like toxicity, pharmacokinetic, and animal model testing under Good Laboratory Practice standards. The goal of preclinical trials is to obtain sufficient safety and efficacy data to justify moving a drug into clinical trials with human subjects.

1. UNIT - I
NEW DRUG
DISCOVERY
AND
DEVELOPMENT
(PART – 2)

2. PRECLINICAL TRIALS (PRECLINICAL STUDIES)
• Preclinical trials or non clinical trials – are laboratory test of
a new drug substance or medical devices, usually done on
animal subjects, to see whether the treatment really works and
if it is safe to test on humans.
• 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. • 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.

4. OBJECTIVES OF PRECLINICAL STUDIES
• The purpose of pre-clinical study 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
• However the main objective is to collect the data to submit to
the FDA for IND filing.

5. Why Preclinical Testing?
To determine whether a drug will move on to studies in
humans or not
Designing phase I clinical trials.
Help to identify criteria for evaluating safety in humans.
Detect overt (hidden) toxicity
Identify, describe and characterize hazards
Establish dose-response estimation of pharmacology and
toxic effects
Assess drug distribution to organ systems
Identify metabolic, kinetic and elimination pathways
Assess carcinogenicity, reproductive toxicity and teratogenic
potential

6. Types of Preclinical Testing
 Short Term Animal Studies (Acute):
-Determine pharmacological action and toxicity
Long Term Animal Studies (Chronic):
- Look for potential side effects that may result from long term
use such as carcinogenicity
- Look for reproductive effects

7. Species Selection
Data in two (2) Species is required
• Why 2 Species?
- Because Species differences in response
•Rodent – almost always Rat because Mouse has poorest
clinical concordance
•Non-rodent – dog, non-human primate e.g. Monkeys, apes

8. 5
4
3
2
1
THERE ARE SEVERAL STEPS INVOLVED WITH
DOING A PRE- CLINICAL TRIAL:
File for approval as an Investigational New
Drug (IND)
Establish Effective and Toxic Doses
Screen the Drug in the Assay
Develop a Bioassay
Indentify a Drug Target

9. Step One: Get an idea for a drug target.
Drugs target specific points in biochemical pathways
Biochemical pathways are series of chemical reactions
occurring within a cell. In each pathway, a principal
chemical is modified by chemical reactions. e.g.
A B C D E
Any step in the pathway, for example from A to B, or B to
C, might be a target for the right drug.

10. Step Two: Develop a Bioassay
•Bioassay is a “live” system that can be used to measure drug
effect.
•It may be a culture of cells or organs or a whole animal.
For example:
Zebra-fish embryos - you can see effect of drugs on bone
density, blood vessel growth and many other systems of the
zebra-fish.

11. Step Three: Screen the drug in the Bioassay.
This is the actual test of the drug on the chosen bioassay.
This will determine if the drug is SAFE and if it is
EFFECTIVE in the bioassay (BEFORE it is ever tested on
humans!)

12. Step Four : Establish Effective and Toxic Doses
Establish what dosage amount of the drug is safe and
what dosage amount of the drug is toxic.
Most drugs have a toxic level or an amount at which the
drug will become harmful instead of helpful.

13. Step Five : File for approval as an Investigational New Drug (IND)
Application is made to the Food and Drug Administration (FDA) as an
Investigational New Drug (IND).
IND must show how the drug:
Is manufactured.
Appears (color, solubility, melting point, particle size, moisture
content).
Formulated (pills, liquid, etc. + inactive ingredients) will be analyzed
for purity, concentration, stability.
Will be tested for safety (this will be the basis for allowing first use in
humans).

14. THE TYPES OF STUDIES INCLUDED IN PRECLINICAL
TRIALS
1.Screening Test
2. Tests on isolated organs, bacterial cultures
3. Tests on animal models of human disease
4. General observational test
5. Confirmatory tests and analogous activities
6. Mechanism of action
7. Systemic pharmacology
8. Quantitative test
9. Pharmacokinetics
10. Toxicity test

15. 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, antisecretory, vasodilator, antibacterial, etc

16. 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.

17. 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.
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.

18. 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.
8. Quantitative test: The dose-response relationship, maximal
effects and comparative efficacy with existing drug is carried
out.

19. 9.Pharmacokinetics:The dose-response relationship, maximal
effects and comparative efficacy with existing drug is carried
out.
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 LD50.
• Organ toxicity is examined by histopathology on all animals.

20. These whole tests are carried out under standardize procedure
under “Good Laboratory Practice” (GLP).
• 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

21. GLP specifically refers to a quality system of 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.