Preclinical trials involve testing potential new drugs on animals before human testing to determine if they are safe and effective. This process involves several key steps: 1) Researchers identify a biological target related to a disease through basic research. 2) They develop a bioassay using cells or animals to test drug effects. 3) Potential drug compounds are screened in the bioassay to see if they act on the target. 4) Effective and toxic doses are established to find a safe range. If successful, 5) approval is sought from the FDA to begin clinical trials in humans.

1. Preclinical Trials

2. What do you think?
• Have you ever had to take a medicine to treat an illness?
• Have you ever wondered how researchers determine if the
medicines you take are safe or not?

3. • Pre-Clinical Trials and Clinical Trials are the processes by which
scientists test drugs and devices to see if they are SAFE and EFFECTIVE.

4. What is a Preclinical Trial?
• Preclinical trial - a laboratory test of a new drug or a new medical
device, usually done on animal subjects, to see if the hoped-for
treatment really works and if it is safe to test on humans.

5. There are two types of Research: Basic and
Applied
Basic Research: discovering new facts about how
things work, how they are made, or what causes a
biological event to occur. Basic research can
explore a topic, explain a topic or describe a topic.
For Example: A researcher discovered that genes
can be turned off or on by small RNA molecules in
the body. This study was conducted on worms. It
led to the Nobel Prize in 2006.

6. “Basic” vs. “Applied”
Research
Applied Research: Taking the
information discovered in basic
research and investigating how to
use it to treat and prevent
sicknesses.
Example: A researcher uses the
information about turning genes
off and on to find a drug that is
used to turn off genes that cause
diseases and disorders in humans.
Segment of DNA.
Many such
segments act as
genes.

7. Where Do We Get New Ideas For Research?
Ideas come from all kinds of scientists and medical professionals who do
research in universities, government labs, and in corporations.

8. Take a Minute to Discuss:
• What is a Pre-Clinical Trial?
• What is the difference between basic research and applied
research?
• What sickness or disease would you like to see an effective
treatment for?

9. There are several 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

10. Steps in Doing a
Pre-Clinical Trial:
• Drugs usually act on either cellular or genetic chemicals
in the body, known as targets,
which are believed to be associated with disease.
• Scientists use a variety of techniques to identify and
isolate individual targets to learn more about their
functions and how they influence disease.
• Compounds are then identified that have various
interactions with the drug targets that might be helpful
in treatment of a specific disease.
Step One: Get an idea for a
drug target.

11. Finding the Right Target Is Not Easy
Parkinson’sDiseaseExample:
Parkinson's disease:
a disease which causes
deterioration of the
central nervous system
over a period of time.
This disease often
impairs the patient’s
movement, speech, and
other functions.

12. • Tremors or shaking occurs when cells in one part of brain die. These cells
communicate using a chemical called dopamine.
• Drugs that replace dopamine work only for a few years.
• Other Parkinson’s symptoms (depression, sleep disorder, digestive problems,
loss of brain function) have other causes.
• Another sign of Parkinson’s disease: many cells have deposits of a protein,
synuclein.
• Four drug companies are developing drugs to counter synuclein, even
though nobody knows if it is a cause or a consequence of Parkinson’s.
• Synuclein could be like a tombstone—a marker, not a cause of cell death.
How is Parkinson’s treated? Where should the
focus be?

13. • 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.
• Examples of different types of biochemical pathways:
A
E B
D C
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.
* See slide
note

14. Step Two: Developa Bioassay
A Bioassayis a “live”systemthat can be usedto
measuredrug effect.
• It may be a culture of cells or
organs or a whole animal.
For example:
• Zebra-fish embryos - you can
see effects of drugs on bone
density, blood vessel growth
and many other systems of the
zebra-fish.
Steps in Doing a
Pre-Clinical Trial:

15. • 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!)
Steps in Doing a
Pre-Clinical Trial:
Step Three: Screen the
drug in the Bioassay.

16. • Most drugs have a toxic level or an amount at which the
drug will become
harmful instead of helpful.
Steps in Doing a
Pre-Clinical Trial:
Step Four: Establish what dosage
amount of the drug is safe and what
dosage amount of the drug is toxic.

17. Toxicity study
• Acute toxicity- Acute toxicity studies are required
for all drugs these studies involve single
administration of the agent up to the lethal level
in at least two species. E.g. one rodent and one
nonrodent.
• Subacute & chronic toxicity- subacute and
chronic testing are required for most agents,
especially those intended for chronic use. Test s
are usually carried out for at least the amount of
time proposed for human application, i.e. 2-4
week (subacute) or 6-24 months (chronic),in at
least two species.

18. 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).
Steps in Doing a
Pre-Clinical Trial:
Step Five: Application is made to the
Food and Drug Administration (FDA)
as an Investigational New Drug (IND).

19. Think Break:
• How are these steps like the steps of the Scientific Method?
• Why would research scientists use a Bioassay instead of a human
subject to test a new drug?
• What percentage of drugs do you think get this far in the process?

20. Review:StepstoNewDrug Discovery
Pre-ClinicalTrials
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)

21. Can you summarize the process?
With a partner or your group, write a summary of
the Pre-Clinical Trial Process. Use the following
words to help you:
Drug
Safe
Effective
Basic Research
Applied Research
Target
Biochemical Pathway
Bioassay
Toxic
Investigational New Drug (IND)