Preclinical Studies in new drug development

1. Preclinical Studies
Presented by:
Ali Safdar
Ehsan Elahi
M. Ramzan
Fayyaz Ahmed
Aqeel Shahzad
Mohsin Ali
Azeem Imam
MPHIL Pharmaceutics
UCP Lahore

2.  Preclinical studies are conducted to define
pharmacological and toxicological effects not only
prior to initiation of human studies but throughout
clinical development.
 Both in vitro and in vivo studies can contribute to
this characterization.
Definition

3. Phases of Drug Development

4. Phases of Drug Development

5.  Whether a drug will move on to studies in humans
 Designing phase I clinical trials.
 Help to identify criteria for evaluating safety in
humans.
Why Preclinical Testing?

6.  Detect overt toxicity
 Identify, describe and characterize hazards
- reversible? - clinically monitor able?
 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
Why Preclinical Testing?

7.  Medical uses/needs for substance
 Commercial potential
 Feasibility for mass production (manufacturing costs)
Major considerations while doing
Preclinical Studies

8.  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
Types of Preclinical Testing

9.  Data in two (2) Species is required
 Why 2 Species?
 Species differences in response
 Rodent – almost always rat
 Mouse has poorest clinical concordance
 Non-rodent – dog, non-human primate
eg. Monkeys, apes
Species Selection

10.  Safety Pharmacology
- functional assessment of major systems
 General Toxicology
- target organs, “chronicity of the toxicity”
 Developmental and Reproductive Toxicology
- fertility and reproductive performance
- embryo/fetal development
- neonatal development
Overview of Study Types

11.  Genetic Toxicology
potential for cancer and heritable mutations
 Carcinogenicity
6 months, 2+ species, same route of administration to be
used in humans)
 Teratogenic Studies
Substance given to pregnant females and during lactation
(usually rats & rabbits)
Study Types Continu……

12. Preclinical Studies continue along
with Clinical Trials

13.  Pharmacodynamics
 Pharmacokinetics
 Single dose toxicity in two species
 Repeated dose toxicity in two species, minimum 2 weeks.
 Local tolerance
 Teratogenicity study if fertile women are included in the
study.
Preclinical studies to be performed
before phase I clinical trials

14.  All genotoxicity studies
 Repeated dose toxicity. Duration depending on
duration of clinical study
Preclinical studies to be completed
before phase II clinical studies.

15.  Fertility studies
 Repeated dose toxicity
 In parallel with phase II and phase III clinical studies,
other toxicity studies are completed
Preclinical documentation before phase
III clinical study

16. Steps involved with doing a Pre-
Clinical Trial:
File for approval as an Investigational New Drug (IND)
5
4
3
2
1
Establish Effective and Toxic Doses
Screen the Drug in the Assay
Develop a Bioassay
Indentify a Drug Target

17. 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.

18. A 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.
Step Two: Develop a Bioassay

19.  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!)
Step Three: Screen the drug in the
Bioassay.

20. 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.
Step Four

21.  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).
Step Five

22.  Get idea for drug target
 Develop a bioassay
 Screen chemical compounds in assay
 Establish effective and toxic amounts
 File for approval as an Investigational New Drug (IND) (leads
to clinical trials)
Review: Steps to New Drug Discovery
Pre-Clinical Trials

23.  Remington, the Science & Practice of Pharmacy, 21st
edition, Vol. 01, Pg. 965-972.
 Pharmaceutical Dosage Forms and drug delivery
systems, 7th edition by Howard C. Ansel
 http://www.fda.gov/ForPatients/Approvals/Drugs/uc
m405658.htm
Reference

25. THANKS