Transcript Clinical Trials PHASE 1

Clinical Trials - PHASE 1
WHAT ARE PHASE I TRIALS ?
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Phase I trials refer to
the first introduction
of an experimental
drug into the human
population.
Subjects are usually
healthy male adult
volunteers.
WHY PHASE I TRIALS?
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The primary concern - assessment of the drug’s
safety and safe effective dose for further phase
studies
To determine what happens to the drugs in the
human body.
To determine the dosage level of the drug.
To evaluate how a new drug should be
administered.
Side effects of the drug.
Problems
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Most problems associated with this phase are
related to the direct pharmacodynamic effect, i.e
inter species differences.
 E.g.
Penicillin oral produces toxic GI bleed in
Guinea pigs but it is well tolerated in man.
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There are certain types of drug activities which
are seen only in man.
 E.g.
changes in mood, arousal, sleep etc.
PRE-CLINICAL DATA
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Pre-clinical evaluation gives
us information on:
The approximate starting dose
for Phase I human trials.
Parameters for potential
adverse effects.
DOSE IN PHASE I
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NOEL No Observed Effect Level
NOAEL No Observed Adverse Effect Level
MRSD Maximum Recommended Starting Dose
MRDD Maximum Recommended Daily Dose
INITIAL HUMAN DOSE
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A starting dose can be
selected low enough to
avoid unnecessary risk.
Generally, first dose can be
related to ED50 in pre
clinical studies.
STUDY SITE
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Should have a well equipped Clinical
Pharmacology Unit.
Be able to conduct tests such as that of
blood/plasma etc.
Medical experts should be around.
Should be well equipped to handle emergencies
or any such eventualities.
REGULATORY ASPECTS
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Under the directives of the Drugs and Cosmetics
Rules, phase I trials are not normally permitted for
foreign companies and is usually reserved for the
new drug substance discover in India.
The 2005 amendment of the Schedule-Y of the
Drugs and Cosmetics Rules made parallel trials
possible in India.
DRUGS UNDERGOING PHASE I
TRIALS AT PRESENT ARE:
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Praneem, a neem based poly-herbal microbicide
being developed by Pune based NARI is in the
phase I stage.
HIV Vaccine (tgAAC09) is now undergoing phase I
trials for safety and immunogenicity assessment in
healthy HIV uninfected volunteers at NARI, Pune.
Gropep is presently carrying out a phase I trial of
its infertility drug- PV903
STUDY TEAM DESIGN
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The team designing a clinical study must
possess a comprehensive understanding of
Medical
consideration
Regulatory requirements
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Therefore, involvement of regulatory affairs
group is important and fundamental to the
principles of good clinical project
management.
EXPERIMENTAL DESIGN
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Phase I studies are carried
out in 2 stages
 Single
rising dose
 Repeat administration
STAGE 1–SINGLE RISING DOSE
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Each volunteer given a single dose of
drug/placebo.
Dose-escalating study design.
Initial dose and route of administration decided
from existing pre-clinical data.
8 -12 volunteers admitted after meticulous
screening.
2-4 volunteers receive placebo and 6-8 volunteers
receive drug under study.
STAGE 1-SINGLE RISING DOSE
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Study subjects admitted in an inpatient clinic,
observed by full time medical staff.
Test and examination done:
 Prior
to start of drug administration
 At interval during the study (e.g. 2h, 4h, 8h,
16h )
 Before discharge
 4-10 hrs after dose.
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Only after results of 1st group analyzed, drug
administered to the next group.
STAGE 2 REPEATED
ADMINISTRATION
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Start after single dose administration results
assessed.
Drug / placebo given repeatedly for 1 or more
weeks
 E.
g. Antibiotics given for 5-7 days
 Anticonvulsants tested for 4 weeks or more
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Interval between doses is usually one half life.
STAGE 2 REPEATED
ADMINISTRATION (contd.)
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Study design - Typically dose escalating studies
Kinetic data obtained from blood and urine
sample collected after 1st and last dose
‘Trough samples’ – blood sample taken
immediately prior drug administration give
information about accumulation and attainment of
steady state blood concentration
Requirements
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All documents of pre-clinical data
Plans, protocols and CRF ’s for phase I studies.
Name, address and bio-data of investigator.
Agreement from the sponsors to inform the drug
controller of any AR’s occurring during ongoing
animal/human studies.
Nature of ‘informed consent’
Agreement to submit annual progress report
FEES
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Regulatory fees payable to the DCGI’ s office for
reviewing submitted documents.
Rs. 50,000/- for phase I studies.
Application to be submitted to the Drugs
Controller General (India) office at Nirman
Bhavan.
Fees to be paid in a Nationalized bank in
government account.
Study Subjects
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Healthy adult volunteers
or patients
Moderately ill patients
likely to benefit from the
drug, can volunteer
Small number - 20 to 80
DOSE INCREMENT
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First 3-4 patients based on on-going experience
in tolerability.
Increase can be 1.5 or 2 times the previous dose
depending on  Pharmacodynamic
effects of the previous dose.
 Margin between projected therapeutic dose.
 Theoretical max human tolerated dose.
ADVERSE EFFECTS
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Appearance of a SAE major challenge in new
drug testing.
If investigational drug responsible for AE,
subsequent administration to be prevented.
Significant AE-subject withdrawn from further
dosing.
Assessment of data and expert consultation done
to decide-role of drug in AE and study
continuation.
ADVERSE DRUG REACTIONS
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Serious toxicity is rare and needs judgment for
proceeding
Interpretation of clinical and lab deviations from
normal range.
Within- subject comparison of data is mandatory.
DATA RECORDING AND STORAGE
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Accurate record of each experiment mandatory
for scientific purpose, statutory and other review
requirements.
Mode and time of entries should be standardized
for future interpretation.
Data should be available in duplicate/triplicate
and store at 2/3 different places to avoid
accidental loss.