Understanding

Pre-Clinical and Clinical

Trials

Presented By:

Mirza Danish Hussain Barlas (Pharm-D , R.Ph, MBA)

Disclaimer

The information within

this presentation is based on the

References, the Presenter's Interest and

Experience.

Pre-Clinical Trials and Clinical Trials are the

processes by which scientists test drugs and

devices to see if they are SAFE and

EFFECTIVE.

The Evaluation of Drug

Safety and Efficacy

The Evaluation of Drug Safety

and Efficacy are Done in 2 Parts:

1. Pre-Clinical Trials

2. Clinical Trials

What is a Preclinical Trial?

Preclinical Trials – research on a new drug

or a new medical device or procedure,

usually done on animals, to learn about

mechanisms of action, determine how well

the treatment works, and see if it is safe to

test on humans.

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.

“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.

Drug Discovery

In general Drug Discovery is brought about by the

following approaches:

1. Random Screening

2. Molecular Manipulation

3. Molecular Designing

4. Drug Metabolites

5. Serendipity

The main focus however lies on the

Identification a Drug Target-Receptor.

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

Identify a Drug Target

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.

Step Two: Develop a Bioassay

A Bioassay is a “live” system that can be used to measure drug

effect. "The determination of the relative strength of a substance

(as a drug) by comparing its effect on a test organism with that of a

standard preparation”.

Bioassays are typically conducted to measure the effects of a

substance on a living organism and are essential in the

development of new drugs. Both are procedures by which the

potency (pharmacology) or the nature of a substance is

estimated by studying its effects on living matter.

2 Types of Bio Assays:

a. Quantal

b. Graded

Steps in Doing a

Pre-Clinical Trial:

Steps in Doing a

Pre-Clinical Trial:

Quantal

-A Quantal assay involves an "all or none response". For example: Insulin

induced hypoglycemic convulsive reaction or the cardiac arrest caused by

digitalis. The response is either +ve or -ve, there is no intermediate response

e.g.—either convulsion occurs or doesn't occur; similarly is with cardiac arrest.

(a) Comparison of threshold response

(b) Comparison of (ED50) or (LD50)

Graded

Graded assays are based on the observation that there is a proportionate

increase in the observed response following an increase in the concentration or

dose. The parameters employed in such bioassays are based on the nature of

the effect the substance is expected to produce. For example: contraction of

smooth muscle preparation for assaying histamine or the study of blood

pressure response in case of adrenaline.

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.

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.

The IND application must contain information in three broad areas:

Animal Pharmacology and Toxicology Studies - Preclinical data to

permit an assessment as to whether the product is reasonably safe for

initial testing in humans. Also included are any previous experience with

the drug in humans (often foreign use).

Manufacturing Information - Information pertaining to the composition,

manufacturer, stability, and controls used for manufacturing the drug

substance and the drug product. This information is assessed to ensure

that the company can adequately produce and supply consistent batches

of the drug.

Steps in Doing a Pre-Clinical Trial:

Investigational New Drug (IND).

Step Five: Application is made to the

Food and Drug Administration (FDA)

as an Investigational New Drug (IND).

Investigational New Drug (IND).

Clinical Protocols and Investigator Information - Detailed protocols

for proposed clinical studies to assess whether the initial-phase trials

will expose subjects to unnecessary risks. Also, information on the

qualifications of clinical investigators--professionals (generally

physicians) who oversee the administration of the experimental

compound--to assess whether they are qualified to fulfill their clinical

trial duties. Finally, commitments to obtain informed consent from the

research subjects, to obtain review of the study by an institutional

review board (IRB), and to adhere to the investigational new drug

regulations.

Once the IND is submitted, the sponsor must wait 30 calendar

days before initiating any clinical trials.

During this time, FDA has an opportunity to review the IND for safety to

assure that research subjects will not be subjected to unreasonable

risk.

Review: Steps to New Drug Discovery

Pre-Clinical Trials

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)

What are Clinical Trials?

Clinical Trials are medical or health-related

research studies done in human beings (or

in animals if the study is a veterinary study).

Why are Clinical Trials

Important? In Clinical Trials, researchers take the results from

basic scientific research and translate them into

ways to prevent, treat, or diagnose disease.

Without them, we would could not ensure safe,

effective treatments for diseases.

The Scientific Method

Clinical Trials are “real

world” applications of the

Scientific Method.

Each time a drug, medical

device or procedure, is

tested, a question is

asked, a hypothesis is

made, an experiment is

conducted, results are

analyzed, and a

conclusion is reached.

Types of Clinical Trials: (as defined by the National Institutes of Health)

Treatment Trials - test new treatments, new

combination of drugs or new approaches to

surgery or radiation.

Prevention Trials - look for better ways to prevent

diseases.

Types of Clinical Trials:

Diagnostic Trials - determine

better tests or procedures for

diagnosing a particular disease

or condition.

Screening Trials - test the best

way to detect or treat diseases.

Quality of Life Trials - explore

and measure ways to improve

the comfort and quality of life of

people with a chronic illness.

Sponsors

Clinical trials are usually

sponsored or funded by

companies that make

pharmaceuticals or medical

devices.

Trials can occur at sites as

varied as hospitals,

universities, doctors’ offices,

community clinics, or in the

offices of clinical-trial

contractors.

Clinical Trials are Done in

Phases:

Clinical Trials are Done in

Phases:

Clinical Trials are Done in

Phases:

Phase 0 A Phase 0 study gives no data on safety or efficacy, being

by definition a dose too low to cause any therapeutic effect.

Drug development companies carry out Phase 0 studies to

rank drug candidates in order to decide which has the best

pharmacokinetic parameters in humans (10 to 15) to take

forward into further development. They enable go/no-go

decisions to be based on relevant human models instead of

relying on sometimes inconsistent animal data.

Clinical Trials are Done in

Phases:

Phase I

Researchers test an experimental drug or

treatment in a small group of people

(approximately 20-100) for the first time. The

purpose is to evaluate its safety and identify

side effects. If this is a veterinary study, it is

conducted in animals.

Phases of Clinical Trials:

Phase II

The experimental drug or treatment is

administered to a larger group of

people/animals (approximately100-300) to

determine its effectiveness and to further

evaluate its safety.

Phases of Clinical Trials:

Phase III

The experimental drug or treatment is administered to

a large group of people/animals (300-3,000 or more)

to confirm its effectiveness, monitor side effects, and

compare it with standard or equivalent treatments.

Research Concepts

In many studies, the new drug is

compared to a placebo. A placebo is a

product that looks like the new drug, but it

does not have the active ingredient in it.

People do not know that they are getting

the placebo.

Sometimes the test compares the new

treatment against an existing treatment to

see if better results can be obtained.

Research Concepts

Blind and Double Blind Trials are frequently

done.

A Blind Trial is a trial in which the patients do not

know if they are receiving the treatment or a

placebo.

A Double Blind Trial is a trial in which the

patients and the researchers do not know who is

receiving the treatment.

Why would the above be good ideas?

Research Concepts

Randomization is the process by which patients

are assigned a group for the Clinical Trial.

Groups are assigned randomly, not purposefully.

Some people will receive the new treatment, some

may receive an already approved treatment, and

some may receive a placebo.

If one treatment is found superior, the trial is

stopped so that the fewest patients possible

receive the less beneficial treatment.

New Drug Application (NDA)

The New Drug Application (NDA) is the vehicle in the United States

through which drug sponsors formally propose that the Food and Drug

Administration (FDA) approve a new pharmaceutical for sale and

marketing. The goals of the NDA are to provide enough information to

permit FDA reviewers to establish the following:

Is the drug safe and effective in its proposed use(s) when used as

directed, and do the benefits of the drug outweigh the risks?

Is the drug’s proposed labeling (package insert) appropriate, and what

should it contain?

Are the methods used in manufacturing (Good Manufacturing Practice,

GMP) the drug and the controls used to maintain the drug’s quality

adequate to preserve the drug’s identity, strength, quality, and purity?

Approval must be gained:

Once a drug has proven satisfactory after Phase III trials,

the trial results are usually combined into a large document

containing a comprehensive description of the methods

and results of human and animal studies, manufacturing

procedures, formulation details, and shelf life.

This collection of information makes up the "regulatory

submission" that is provided for review to the appropriate

regulatory authorities like the U.S. Food And Drug

Administration (FDA) so they can then grant the sponsor

approval to market the drug, device or treatment.

The Results!

For approximately every 5,000 to 10,000

compounds that enter preclinical testing, only

one is approved for marketing.

Cost of the failures has to be borne by the

price of the one success.

Phases of Clinical Trials:

Phase IV

After a drug is licensed (approved by the FDA) or treatment

is launched, researchers track its safety, seeking more

information about a drug or treatment’s risks, benefits, and

optimal use. These long-term studies involve large groups

of participants and are designed to reveal if any unexpected

side effects occur in a small percentage of individuals.

Sep 2015

Phases of Clinical Trials:

Phase V

Is a growing term used in the literature of

translational research to refer to comparative

effectiveness research and community-based

research; it is used to signify the integration of a

new clinical treatment into widespread public

health practice.

May 2014

Timeline Estimate

Below are some estimates on the amount of time it takes for this process

Pre-clinical Trials - 4.5 years

Phases I-III - 8.5 years

FDA Approval - 1.5 years

Phase IV – Ongoing

How long is this whole process?

Approx.12-15yrs

Costs

On average, pharmaceutical

companies are spending anywhere

between $100 (100x96=9600PKR)

and $800 (800x96=76800PKR)

million per each drug tested!

Spending on clinical trials in the

U.S. is forecasted to rise to $32

(32x96=3072PKR) billion.

References

Information from this presentation comes from:

http:clinicalresearch.nih.gov/how.html

http://clinicaltrials.gov/ct2/info/understand

http://www.dddmag.com/the-cost-of-clinical-trials.aspx

http://www.fda.gov

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForm

s/Forms/UCM082348.pdf