Clinical Research

an
Overview
 What is clinical research?
Branch of healthcare science that determines
the safety and effectiveness of medications,
devices, diagnostic products and treatment
regimens intended for human use.
Prevention
Treatment
Diagnosis
Palliative
 Broad goal

To take the products of the discovery cycle from

the laboratory to the prescription

Pre-clinical: Drug discovery pathways

Pre-clinical toxicology and safety

To do so in a manner that is ethical and humane

 James Lind and Scurvy
The First Randomized Trial in 1747

Group 1: quart of cider daily

Group 2: 25 drops of elixir of vitriol (sulfuric acid)
Group 3: 6 spoonfuls of vinegar
Group 4: 1/2 pint of seawater
Group 5: 2 oranges and a lemon
Group 6: a spicy paste plus a drink of barley water.
Digitalis (1785)
Foxglove

A cardiac glycoside
Unethical human experiments
Syphilis Trial
 Unethical Human Experiments

*Nazis trial *Willowbrook study

Thalidomide tragedy
 A Timeline of Historical Landmarks in
Clinical Research
• 1754 – James Lind conducts the first ever clinical trial
on scurvy-affected sailors
• 1932 – Between 1932-72, the US Public Health Service
conducts a syphilis experiment on 399 unwitting black
men
• 1945 – The Nuremberg Code drafted after Nazi
atrocities in the cloak of human experimentation come
to light
• Late 1950s – The thalidomide tragedy occurs where
between 1956-62, more than 10,000 children were
born with malformations
• 1969 – The Belmont Report introduced to confer the
principles of autonomy, beneficence and justice
• 1975 – The Declaration of Helsinki comes into being to
accord top priority to the principles of self-
determination and freely-given informed consent
• According to the US National Institutes of
Health (NIH), clinical trials are of five types:
– Treatment trials
– Prevention trials
– Diagnostic trials
– Screening trials
– Quality of life trials
 A Guide to Clinical Research
• The International Conference on
Harmonization and Good Clinical Practice (ICH
GCP) guidelines were laid out in the 1980s by
a six-member party that included the US,
Europe and Japan
• This was deemed important because of the
acute need to independently evaluate
medicinal products before their mass market
consumption
 The Clinical Trial Ladder
Flow chart
Phase IV

Phase III

Average
of 8 years Phase II
for the
whole
process
Phase I

Phase 0
 Phase 0
• Phase 0 studies are exploratory first-in-human trials
that are designed to expedite the development of
promising therapeutic agents
• Typically 10-15 volunteers are utilized in the study to
evaluate the pharmacokinetics of the drug
• The dosage given is sub therapeutic that has almost
no risk of side effects
• It is reported that 75 per cent of the 20 leading
pharmaceutical companies have now used micro
dosing in drug development and have been endorsed
by the FDA
 Phase I
• This is a study phase where about 20-80
healthy volunteers are recruited to receive the
investigational drug
• Exceptions include HIV and oncology trials and
end-stage diseases for obvious reasons
• Single ascending dose (SAD) and multiple
ascending dose (MAD) studies are carried out
to better evaluate the ADME profile of the
investigational new drug (IND)
 Phase II
• Also designated a therapeutic exploratory phase, this
stage involves a larger group of patients (20-300)
• Phase II safety assessments are continued to
determine how well the drug works
• In recent times, these studies have been divided into:
 Phase IIA – Designed to assess drug dosing requirements
 Phase IIB – Designed to study drug efficacy in patients
 Phase III
• This phase, also called the therapeutic
confirmatory phase, involve large patient
groups (300-3000)
• This stage is the most comprehensive critical,
and expensive in the whole business of clinical
trials
• It’s at this stage that regulatory submissions
are made that set the tempo for drug approval
by the regulatory authority to the sponsor
 Phase IV
• These trials involve post-marketing surveillance and
ongoing technical support for an IND
• This stage is designed to detect long-term or rare
adverse events associated with the drug and
reported to the appropriate authority (such as the
Uppsala Monitoring Committee)
• Effectiveness of a drug as opposed to its efficacy is
the primary focus area in this phase
 Fundamentals for clinical research….

• A hypothesis
• Definition of the primary endpoint
• A protocol
• Data collection
• Data analysis
• A study report
 Issues
Cost: About $350 m (X __Rs) on average to get a
drug to market
Time: 12 years
Success rate : 5 in 5,000 drugs that enter
preclinical testing progress to human testing;
one is approved - 1 in 5,000.