1. Phase 0 and Phase 1 clinical trials are the earliest stages of testing in human subjects. Phase 0 trials involve microdosing to evaluate pharmacokinetics and pharmacodynamics, while Phase 1 trials determine safety and tolerability in a small number of subjects. 2. Phase 1 trials aim to determine the maximum tolerated dose, evaluate pharmacokinetic properties, and assess safety and tolerability. Subjects are normally healthy volunteers and are closely monitored. 3. Parameters assessed include adverse effects, pharmacokinetics like Cmax and Tmax, and biomarkers if available. The data obtained guides the decision to progress further clinical development of the drug.

1. PHASE 0 AND PHASE 1 CLINICAL
TRIAL
Dr. Yash N. Panchal
Junior Resident
Department of Pharmacology
AMC MET Medical college
02/09/2021

2. • History and introduction of clinical trial
• Pre-requisite to conduct clinical trial
• Phase 0 trial – Phase 1 trial -
Purpose Purpose
Features Objectives
Objectives Study populations
Procedures CPUs
Analytical methods Formulations
Advantages Parameters assessed
Limitations
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3. 3

4. • Any research study that prospectively assigns human participants or
groups of human participants to one or more health related
interventions to evaluate the effects on health outcomes (WHO)
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5. 5

6. To diagnose or detect disease
To treat an existing disorder
To prevent disease or early death
To change behavior, habits, or other lifestyle factors
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7. Diagnostic trial-
to find better diagnostic tool to
diagnose disease
Preventive trial-
Vaccine trial
Treatment trial-
Done to test new drug, new
treatment
Quality of life trials-
Study the effect of lifestyle changes
and treatments on quality of life
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9. A clinical trial can begin only when all preclinical studies shows
satisfactory results, and approval has been received from DRA
 DRA- India (DCGI), USA(FDA), UK(CSM)
 Prior to conduct of a clinical trial, an IND must be filled with the DRA, to
request permission to begin Human testing
 Filled by Sponsor/Manufacturer
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10. )
1. An introductory statement and general description of the plan for
studying the drug or biologic
2. Source, chemical structure, manufacturing data and details on the
purity of drug
3. Pre-clinical study details of the drug in terms of pharmacokinetics,
pharmacodynamics, efficacy and toxicity
4. Specification on dosage forms in which it has to be administered to
human volunteers
5. Description on dose and route of administration of the drug
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11. 6. A certification that “ Informed consent ” will be obtained from each and
every human volunteers and Ethics of research in human beings will be
strictly followed
7. Names and qualifications of every investigators and facilities involved in
clinical trial
8. An investigator’s brochure containing information pertaining to the
investigational drug formulation, PK, PD, safety and toxicity from previous
studies
9. Agreement from sponsor to submit annual progress report regularly
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12. Surveys had showed in R&D expenditure but numbers of INDA static/
Nearly one third of INDs failed in Phase 1 trial , mainly due to abnormal
PK/PD and safety profiles
If drug development, were to be terminated at Phase 1 stage, then human
volunteers would have been unnecessarily exposed to failed drug and
large number of animals would have been saved
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14. USFDA
Birth of novel approach called Phase 0/ Micro-dosing studies
The principle of human micro dosing is that safely administering micro-
doses of INDs to human to get valuable information on human
pharmacokinetics, pharmacodynamics at a much earlier stage
• Central to this approach is the concept that –
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15. • Caused teratogenic malformations in rat,
mice, dog, and monkeys
• No such incidents reported in humans
ASPIRIN
• Experiment in mice : Extensive liver damage
• Decades of human use have proven its
safety
FUROSEMIDE
• Discovered in 1929
• Not used till 1939 because of its
ineffectiveness in curing infected rabbits
PENICILLIN
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16. • Is dose of the drug that is 1% (1/100th)
of the pharmacologically active dose
determined from animal model and
in vitro system, up to maximum of
100 mcg or 30 nanomole for protein products
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17. • Because human micro dosing studies are performed prior to Phase 1
studies, hence are termed as Phase 0 study
• Are also termed as Exploratory IND studies
• Sub-pharmacologically active dose of drug is administered and samples
(typically plasma) are collected and analyzed for parent drug or
metabolites with no therapeutic or diagnostic intent
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18. To assist the GO vs NO-GO decision making process of drug’s fate in the
development process very earlier
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19.  First in human trial conducted prior to traditional Phase 1 study
 Conducted in limited number of Human participants (10-15)
 Have limited dosing duration (< 7 days )
 Involves a very small dose ( 1/100th of the dose required to yield a
pharmacological effect of the test substance with a maximal dose of < 100
mcg
 Are designed to evaluate PK and/or PD properties of selected
investigational agent before Phase 1 study
 Have no therapeutic or diagnostic intent
 Often take less than 6 months to complete
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20. 1- To evaluate Pharmacokinetic and Pharmacodynamics of candidate drug
2- Evaluating human PK and/or PD of two or more analogs to select the most
promising candidate for further clinical development
3- Eliminating bad agents early in clinical development because of poor PK or
PD properties
e.g- lack of target effect, poor bioavailability, rapid clearance of drug
4- Determining dose range, sequence of administration, and PK associated
with target or biomarker (PK-PD correlation) 20

21. 1- Pharmacokinetics or Imaging
• Evaluate human biodistribution and target-binding ( to molecular target
and target tissues ) characteristics using sensitive imaging techniques
• Preclinical toxicology studies should demonstrate that a dose 100 times of
the proposed dose does not induce adverse effects
2- Pharmacologically relevant dose
• Evaluate human PK of two or more analogues to select a lead agent
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22. 3- Pharmacodynamic end-point studies
• Evaluate whether the new molecular entity modulates its intended target
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23. After the drug candidate has been selected and animal PK data is achieved,
possible human therapeutic dose is determined
A micro dosing clinical trial application ( Exploratory IND) should be submitted
Micro dose is calculated from human therapeutic dose
Bio markers and Bio-analytical methods should be determined, standardized
and validated
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24. Phase 0 study involves 10-15 healthy volunteers, consent of them is taken
Limited duration of dosing (e.g- 1-7 days ); in cancer chemotherapy usually
one cycle only
Bioanalytical samples are obtained pre- and post- dosing
Samples are analyzed by bio-analytical methods for identification of the
predetermined biomarkers
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25. • Low dose administered in Phase o study, will lead to low plasma-drug
concentrations
• Therefore sensitive analytical methods are necessary in order to make the
requisite measurements over an appropriate time
• Sensitive analytical technologies include AMS ( Accelerator mass
spectrometry ) and PET ( Positron emission tomography )
• Both of these rely on assessment and analysis of radio isotopes
incorporated into the drug under study
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26. • In case of AMS, {14C} is the most useful isotope for drug metabolism
studies , whereas for PET {11C} is proving to be the most useful
• AMS is used for determining PK data by taking body samples over time,
processing the sample in the laboratory and then analyzing their drug
content
• PET provides primarily PD data, receptor occupancy data through real-
time imaging and some limited PK data
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27. 1
• Reduces the clinical trial cost and time of drug development
2
• Reduces unnecessary exposure of drug to large number of
participants
3
• It establish if the agent is modulating its target or not, so further
clinical development can be decided at early stage
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• Risk of adverse events is negligible
5
• Requirement of pre-clinical safety data for microdosing is less
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28. • By incorporating the innovative idea of Phase 0 trials, the main beneficiary
will eventually be the patient population at large
• If the Phase 0 trial study reports identify an Investigational new drug as
not being of therapeutic worth, the patient population may certainly be
benefited through the minimization of the study participants recruited to
subsequent trials on the critical path
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29. • Absence of therapeutic or diagnostic intent discourages the volunteers to
take part in trial
• Very few biomarkers are available to predict the efficacy of some drugs(
anti-cancer drugs), and modulation of bio-marker in such a low dose in 7
days is further a barrier
• Micro dose not always correctly measures PK/PD behavior of the
therapeutic dose of the drug, because at micro dose, most of the
compounds dissociate and dissolve rapidly, so fast and extensive absorption
and it ( absorption, Cmax, Tmax, AUC ) depends on dissolution
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30. • Developing radio-isotope for analytical methods like AMS and PET are
costly and needs specialized mechanisms,
these tracers also have a shorter tracer half life and low specificity (
chance of including metabolites also )
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31. • No diagnostic and/or therapeutic intent or benefit from Phase 0 trial
• Risk from research related interventions, for instance repeated tumour
biopsies ( in cancer studies )
• Proper informed consent process of phase 0 must include :
1- Clear explanation of rationality of the study
2- Proper explanation that this is not therapeutic trial, but experimental
3- Absolutely no anticipated direct clinical benefit
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32. • It is the first step in testing (if phase 0 not conducted ) a new intervention
in humans that does not benefit human volunteers ( Non-therapeutic trial
)
• Also known as Human pharmacology and safety study
• The premise where phase 1 trial is conducted is called as Phase 1 unit
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33. To determine whether drug is safe to check for its efficacy in Phase 2 trial or
not
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34. 1- To assess safety of the drug
2- To assess tolerability of the drug
3- To calculate MTD ( Maximum tolerated dose ) of the drug and dose range
4- To evaluate PK ( Pharmacokinetic properties ) and PD ( Pharmacodynamic
properties ) of the drug
This objectives provide firm basis for investigators to determine further
testing of drug on humans ( to decide go- vs non-go- )
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36. Pre-clinical work that establishes the new molecular entity to be safe and
tolerable in animal and in vitro models
• Inclusion criteria : Normal healthy volunteers ( 20-100 participants ),
uniformity of subjects about age, sex
• Exclusion criteria : Women of child bearing age, children
• Exception : Patients in case of study of toxic investigational chemical entity
( study for anti-cancer drugs )
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37. • Subject who enter phase 1 trial need to be fully informed that these
studies usually the initial clinical experiments in human
• Expected side effects as noted in pre-clinical studies are presented and
the possibility of other unpredictable side effects can occur must be stated
• Preferably be explained by clinical staff at the study site rather than the
sponsor and must contain rationale for the start dose and maximum dose
in lay language
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38. Studies are conducted in clinical trial unit known as CPUs ( Central
pharmacological unit )
 CPUs are run by CRO ( Contact research organization ), who are
conducting clinical trial on behalf of Sponsor/Pharmaceutical company
 Studies are conducted under supervision of trained Clinical
Pharmacologists
 Study participants receives 24 hr. medical attention and oversight by full
time staff
 Volunteers are paid an inconvenience fees for their time spent and pay
depends upon the length of the participation
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39. • Inpatient stay facility
• Facilities and personnel for acute emergency coupled with ICU
• Facilities to monitor all physiological functions and signs
• Facilities for routine investigation of hematological, biochemical
parameters, ECG, X-ray, urine analysis
• Drug specific biomarker assessment facility
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40. • Mostly, randomized double
blind placebo control trial
• May be open labeled trial
Type of
Phase 1 Trial
• On average it takes around 1-
1.5 years to complete the
trial
Duration of
Phase 1 Trial
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41. Formulations of IND used
• Intravenous :
o Most flexible as
1- Dose can be adjusted easily
2- Administration can be stopped
immediately if any adverse events occurs
• Oral :
o Oral powder reconstituted as suspension or
solution is administered to the subject
o Tablet formulations may be used as well 41

42. Involves 5 steps
1- Determination of NOAEL ( No Observed Adverse Effect Level )
• NOAEL - highest dose that does not produce adverse effect
• Calculated from each species tested
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43. 2- Conversion of NOAEL to HED
• HED- Human Equivalent Dose
• Formula :
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44. 3- Select most appropriate species
• Pick one HED for subsequent derivation of the MRSD
• This HED is chosen from the most appropriate species
4- Apply safety factor
• After calculating HED of the NOAEL in most appropriate species,
Safety factor will be applied,
To provide a margin of the safety for the protection of human subjects
receiving the initial clinical dose
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45. • Due to
1- Difficulties in detecting certain toxicities in animals
2- Unexpected toxicities
3- Interspecies differences in ADME
• MRSD in calculated, by dividing the HED by the safety factor
• In general safety factor of 10 is used to divide HED, but safety factor of 50
should be applied for small molecules
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46. • E.G.- if NOAEL of a drug in mouse model is 15 mg/kg then,
HED will be – 15 × 0.08 = 1.2 mg/kg
MRSD will be – 1.2/10 = 0.12 mg/kg
• Alternatives :
1- Micro dosing / Phase 0 study – Using 1/100th dose
2- MABEL- minimum anticipated biological effect level / MED ( Minimum
effective dose )
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47. • Evaluation of ADME of drug
• Most important evaluation is
metabolism and clearance to
anticipate possibility of accumulation
of drug or its metabolite
• These assist in formulation development
and to determine dosage in different age group
• Study of food effect on bioavailability is also determined here
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48. 1- Cmax ( maximum plasma concentration achieved )
2- Tmax ( Time required to reach Cmax )
3- Vmax ( maximum rate of absorption of the drug )
4- AUC ( Are under the curve )
5- Vd ( Volume of distribution of the drug )
6- t half ( Half life of the drug )
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49. 1- ADME Study :
• Objective – to understand the metabolism and full clearance mechanism
of the drug and its metabolites in human and to anticipate possibility of
the accumulations of the same
• Information gained –
Primary mechanism(s) of elimination of drug from the body
Proportion of parent drug converted to metabolites
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50. 2- Bioavailability/ Bioequivalence ( BA/BE ) Study :
• Objective –
To evaluate the rate and extent of absorption of the drug from a test
formulation
3- Food effect study :
• Objective-
To evaluate the effect of food on rate and extent of drug absorption from
a given formulation
• Information gained –
Effect of food on the BA of oral drugs and whether to administer drug on
empty stomach or without regards to meal
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51. 4- Renal impairment study :
• Effect of renal impairment on drug clearance, dosage recommendations
for various stages of renal impairment
5- Hepatic impairment study :
• Effect of hepatic impairment on PK of parent drug and its metabolites
• Dosage recommendations for the same
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52. • Blood samples are collected and stored
• Done to identify appropriate and validated biomarker for determination
of the drug activity and efficacy
• Secondary objective of phase 1 trial
• If easily measurable parameters ( e.g- BP, FBS ) are available, and if
changes occurs with a short duration and low dose of the drug exposure,
then drug activity can be assessed earlier
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54. • Single dose is given, and effects are observed
• The assessment is mainly based on DLT (Dose limiting toxicity)
• If PK data is in line with predicted safety value, then dose is increased in
next group of cohort
• Dose escalation is continued till MTD (Maximum Tolerated Dose ) is
defined
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57. • MTD- Highest dose of the drug that produce desired therapeutic effect
with acceptable, tolerable and predictable adverse effects
• MTD determination is important objective of Phase 1 study
• The MTD measured, will be recommended as the starting dose for
subsequent study in Phase 2 trial
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59. • Maiti Rituparna.2020. Postgraduate Topics in Pharmacology. 3rd ed. : Paras
Medical Books
• Postgraduate Pharmacology 1st Edition 2020 by Sougata Sarkar
• Tripathi, K. D. 2018. Essentials of Medical Pharmacology. 8th ed. New Delhi,
India: Jaypee Brothers Medical.
• Satoskar, R., Rege, N., & Bhandarkar, S. (2017). Pharmacology and
Pharmacotherapeutics (25th ed.). New Delhi, India: Elsevier.
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