CLINICAL
RESEARCH
DEFENITION:
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Any investigation in human subjects
intended to discover or verify the
clinical,pharmacological and/or other
pharmacodynamic effects of an
investigation products.
OVERVIEW
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Phase I: Studies in normal healthy
volunteers to understand pharmacology.
Phase II: Dose ranging efficacy safety
studies to determine the optimal dose for
a particular indication.
Phase III: Large scale multicentric
comparative studies to assess efficacy
safety of the study drug v/s currently
accepted treatment.
Phase IV: Post Marketing Studies.
PRIOR TO PHASE I
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1.
2.
3.
The following pre-clinical studies must be
completed before Phase I studies can
begin (in US).
Single dose toxicity in 2 mammalian
species.
Safety pharmacology studies to include
assessment of effects on vital functions.
Pharmacokinetic studies(ADMEAbsorption,Distribution,Metabolism,
Elimination).
4.
5.
6.
7.
Repeated toxicity studies in two species
(one non-rodent) for 2-4 weeks.
Local tolerance studies using route of
administration relative to proposed clinical
administration.
In vitro tests for evaluation of mutation and
chromosomal damage (genotoxicity).
Carcinogenicity studies. (in particular
cases only).
IND APPROVAL
PHASE I
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The investigational Product (drug) is given
to human for first time.
Done in 20-100 subjects.
Usually healthy volunteers.
GOALS OF PHASE I
STUDY
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Metabolic & Pharmacological action of the
drug in human are studied .
Finding out Maximum Tolerated Dose (MTD).
Assessing Adverse Effects associated with
different doses.
Pharmacodynamic (PD) & Pharmacokinetic
(PK) activity of the drug is thoroughly studied
(ADME).
Safe dose is identified.
THE TRIAL
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Sponsor starts the phase I study after
getting approval from the authority.
The subjects are enrolled in the study after
taking Informed Consent.
A process in which a subject voluntarily
confirms his/her willingness to participate
in a particular trial, after having been
informed of all aspects of the trial that are
relevant to the subject’s decision to
participate .
SUBJECTS ENROLLMENT
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Male volunteers between the age of 18 and 35 and not
on current medication,do not abuse alcohol or other
drugs and show no clinically significant haematological or
chemical pathological abnormality.
Subject must be screened for serological evidence of
past or present hepatitis.
Its recommended HIV screening be performed and
investigators must ensure that volunteers fully
understand the meaning of both +ve and –ve results.
US FDA defined normal subjects are those who are free
from abnormalities which would complicate the
interpretation of the data from the experiment or which
might increase sensitivity of the subject to the toxic
potential of the drug.
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Phase I trials most often include healthy volunteers,
however, there are some circumstances when real
patients are used, such as patients who have endstage disease and lack other treatment options.
This exception to the rule most often occurs in
oncology (cancer) and HIV drug trials.
Volunteers are paid an inconvenience fee for their
time spent in the volunteer center.
Pay ranges from a small amount of money for a
short period of residence, to a larger amount of up
to approx £4000 depending on length of
participation.
Place of Investigation
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The first administration of drug to man should take
place in a specialized unit devoted to such studies.
The staff should include clinical pharmacologists
(who are physicians) and nurses experienced in
carrying out phase I studies.
Since a particular dose of a drug cannot be
administered until the results of all important
investigation relating to the previous dose of the
age known so facilities such as chemical pathology
and haematology departments must be near
enough to enable rapid evolution.
PHASE I- TRIAL
DESIGN
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SAD
MAD
Open trials
Crossover trial
Food effect
SAD
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Single Ascending Dose
SAD studies are those in which small groups of subjects
are given a single dose of the drug while they are
observed and tested for a period of time.
Pharmacological activity of the drug is tested.
If they do not exhibit any adverse side effects, and the
Pharmacokinetics data is roughly in line with predicted
safe values, the dose is escalated.
Then a new group of subjects is then given a higher
dose
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This is continued until pre-calculated
pharmacokinetic safety levels are
reached, or intolerable side effects
start showing up (at which point the
drug is said to have reached the
Maximum tolerance dose (MTD).
MAD
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Multiple Ascending Dose
In these studies, a group of patients receives multiple
low doses of the drug.
Studies are conducted to better understand the
pharmacokinetics & pharmacodynamics of multiple
doses of the drug.
Blood, and other fluids samples are collected at various
time points and analyzed to understand how the drug is
processed within the body.
The dose is subsequently escalated for further groups,
up to a predetermined level.
OPEN TRIALS
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In un-blinded trials, often described as open trials,
both doctors and participants know what
treatments are being given.
One of the problems with an open drug trial is that
many participants may not want to take placebos,
because they presume the drug will be better.
Open trials, like single-blind trials, are considered
to be more prone to error than double-blind
procedures.
CROSS OVER TRIAL
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In a cross over trial, each participant gets both
treatments being tested.
Some participants are assigned at random to receive
drug A and later, drug B.
Others receive B, then A.
To produce valid results, the effect of the first drug
must end before the second drug is taken, and viceversa.
This requirement can be hard to satisfy, and is one
reason crossover trials are not often used.
FOOD EFFECT
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A short trial designed to investigate any differences
in absorption of the drug by the body, caused by
eating before the drug is given.
These studies are usually run as a crossover study,
with volunteers being given two identical doses of
the drug on different occasions; one while fasted,
and one after being fed.
OUTCOME FROM PHASE I
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Safety and tolerability studies.
Bioavailability/bioequivalence studies.
Pharmacokinetic and pharmacodynamic studies.
Dose-ranging studies.
Maximum Tolerance Dose (MTD).
Drug-drug interaction studies.
Drug-food interaction studies.
SAFETY STUDIES
TOXICITY STUDIES
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General toxicology studies are done.
Genotoxicity & reproductive toxicity are
studied.
Carcinigenicity is tested- mutagen or not.
BIOAVAILABILITY /
BIOEQUIVALENCE STUDIES.
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Is the rate and extent of drug
administered by non-systemic route
that enters systemic circulation.
Required to calculate dose of the drug.
Bioequivalence refers to the same
bioavailability of two formulations of
the same drug.
PHARMACODYNAMICS
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What the drug does to the body,
i.e,
mechanism of action and
pharmacological effects of a drug.
PHARMACOKINETICS
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Deals with what the body does to the
drug
Absorption
Distribution
Metabolism/ biotransformation
Elimination
Maximum Tolerance
Dose (MTD).
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It is helpful to determine the tolerability
of the dose range expected to be
needed for the later clinical studies.
It also determine the nature of adverse
reaction that can be expected.
These studies include both single and
multiple dose administration .
CLINICAL HOLD
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Clinical Hold : Is to prohibit the study from proceeding
or stop a trial that has started.
In Phase 1 studies, CDER can impose a clinical hold.
Clinical hold is done for the reasons of safety, or
because of a sponsor's failure to accurately disclose
the risk of study to investigators.
Although CDER routinely provides advice in such
cases, investigators may choose to ignore any advice
regarding the design of Phase 1 studies in areas
other than patient safety.
CLOSURE OF PHASE I
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When the data needed are collected the
study can be proceeded to phase II.
All the data generated are submitted to
authorized people and study is
evaluated.
CONCLUSION
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Phase I refers to the first introduction of
a drug into humans. Normal volunteer
subjects are usually studied to
determine pharmacological action of
drugs at which toxicity is observed.
Such studies are followed by doseranging studies in patients for safety
and this is crucial phase in drug
development which has to be done
most carefully.