Phase 0 clinical trials, also known as human microdosing studies, involve administering single subtherapeutic doses of an experimental drug to a small number of healthy volunteers rather than patients. They are designed to establish early on if a drug behaves as expected in humans based on preclinical studies. Phase I trials then begin the first introduction of an experimental drug into humans, normally using a small group of 20-100 healthy volunteers, to assess safety, tolerability and safe dosage levels. Accurate record keeping of trial data is important for scientific and regulatory purposes.

2. Phase 0
• Are also known as human micro dosing studies
• Are designed to speed up the development of promising
drugs by establishing very early on whether the drug or agent
behaves in human subjects as was expected from preclinical
studies.
• Distinctive features of Phase 0 trials include the
administration of single sub therapeutic doses of the study
drug to a small number of subjects (10 to 15)
• At this early stage of testing, the people chosen are usually
healthy volunteers rather than individuals suffering from the
condition the drug is indicated for

3. • Due to the unknown risks surrounding use of the drug, very low
amounts of the drug are used for minimal durations of less than seven
days, to minimize any adverse side effects that exposure to the drug
may cause
• Low doses that were found to be nontoxic in the animal studies are
used.
• The aim of Phase 0 trials is not to test the therapeutic effects but to
check that the drug behaves as expected in humans
• A Phase 0 study gives no data on safety or efficacy, being by
definition a dose too low to cause any therapeutic effect

4. • Phase I trials refer to the first introduction of an experimental drug into the
human population.
• Normally, a small group of 20–100 healthy volunteers
• These trials are often conducted in a clinical trial clinic
• 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

5.  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 bleeding in
Guinea pigs but it is well tolerated in man.
 There are certain types of drug activities which are
seen only in man.
E.g. changes in mood, arousal, sleep etc.

6. Pre-clinical evaluation gives
us information on:
 The approximate starting
dose for Phase I human
trials.
 Parameters for potential
adverse effects.

7.  A starting dose can be
selected low enough to
avoid unnecessary risk.
 Generally, first dose can
be related to ED50 in pre
clinical studies.

8.  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.

9.  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.

10.  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.

11.  The team designing a clinical study
must possess a comprehensive
understanding of
 Medical consideration
 Regulatory requirements
 Therefore, involvement of
regulatory affairs group is important
and fundamental to the principles of
good clinical project management.

12.  Phase I studies are
carried out in 2 stages
Single rising dose
Repeat
administration

13.  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.

14.  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.
 Only after results of 1st group analyzed,
drug administered to the next group.

15.  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(EPILEPTIC) tested for 4
weeks or more
 Interval between doses is usually one
half life.

16.  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

17.  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

18.  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.

19.  Healthy adult
volunteers or patients
 Moderately ill
patients likely to
benefit from the
drug, can volunteer
 Small number - 20 to
100

20.  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.

21.  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.