phase 0 clinical trials

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Dr.Swaroopa,
MD Pharmacology, 1st year Pg.,
Rangaraya medical college.

2. CONTENTS
• Introduction
• Features and objectives
• Types
• Procedures
• Approaches for phase 0
• Ethical considerations
• Analytical methods
• Micro dosing & regulatory guidelines
• Advantages of micro dosing
• Emerging uses of micro dosing
• Limitations of micro dosing
• Conclusion
• References
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INVESTIGATIONAL NEW DRUG APPLICATION :-
Once the pre clinical testing is over, the sponsors are required to submit Investigational
New Drug Application (INDA).
The INDA must contain information in 3 broad areas :-
1) Preclinical data :- includes data obtained from animal studies consisting of pk, pd &
toxicological data.
2) Manufacturing data :- includes data regarding composition, manufacturing process,
stability & the shelf life of the drug product.
3) Protocol of clinical trials :- includes detailed protocol including qualifications of
clinical investigators.

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There are 3 types of IND application :-
1) An Investigator IND application :- It is submitted by a physician who both initiates &
conducts an investigation & investigational drug is administered or dispensed.
2) Emergency use IND application :- It allows the FDA to authorize use of an experimental
drug in an emergency situation that does not allow time for submission of an IND
application.
3) Treatment IND application :- It is submitted for experimental drugs showing promise in
clinical testing for serious or immediately life threatening conditions while the final clinical
work is conducted & the FDA review takes place.
- The purpose is to facilitate the availability of promising new drugs to desperately ill
patients as early in the drug development process.

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Along with the IND application, the sponsor submits the statement of the investigator (investigator’s
undertaking) in Form 1572.
CDER (Centre for Drug Evaluation and Research) is division of the FDA that reviews New Drug Applications to
ensure that the drugs are safe and effective.
Applicant(drug sponsor)
IND
Review by CDER
Medical chemistry Pharmacology/toxicology statistical
SAFETY REVIEW

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Sponsor notification :- once a clinical hold is placed on a commercial IND application, the sponsor
will be notified immediately by telephone by the division director.
The grounds for imposition of clinical hold :-
• Human subjects are exposed to an unreasonable and significant risk of illness or
injury
• Clinical investigations are not qualified.
• Investigator brochure is misleading or materially incomplete.
• IND does not contain sufficient information to assess risks.
• Protocol is deficient to meet objective of trial.
• CDER will contact sponsor within 30 day initial review period.

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 A DRUG PASSESS THROUGH 4 PHASES IN HUMANBEINGS DURING THE COURSE OF ITS
LIFE(PHASE 1-4)
 A NEW PHASE, PHASE 0 IS RECENTLY BECOMING POPULAR. THOUGH NOT
MANDATORY, VARIOUS REGULATORY AUTHORITIES ARE ACCEPTING THE DATA
GENERATED DURING THIS PHASE & ALSO ISSUED GUIDELINES FOR THIS.
PHASES OF CLINICAL TRIALS

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PHASE0 / MICRODOSING
Also called as Microdosing studies or Exploratory Investigational New Drug studies.
MICRODOSE :- A microdose is defined as less than 1/100th of the dose calculated to yield
a pharmacological effect of a test substance & a maximum dose of < or equal to 100
micrograms.
INTRODUCTION :-
 Exploratory IND studies are clinical trials that involves limited human exposure & have
no therapeutic or diagnostic intent.
 The purpose of phase 0 study is to assist in the GO versus NO-GO decision making
process of a drug’s fate earlier in the development process.
 Uses relevant human models instead of relying on an inconsistent animal data.

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Phase 0 is a recent designation for exploratory,
first-in-human trials conducted in accordance with the
united
states Food and Drug Administration’s(FDA)2006
guidance
on Exploratory Investigational New Drug(IND) studies.
Phase 0 studies are also known as pre-phase 1 trial or a

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FEATURES :-
 Conducted before phase 1 studies
 Conducted in a limited number of subjects (10-15)
 Have limited dosing duration (< 7days)
 Involves very small dose
 Help to confirm the end points, such as mechanism of action, pharmacology, bioavailability,
pharmacodynamics & metabolic microdose assessments.
 Have no therapeutic or diagnostic intent.
 Enable a faster and cost effective path to early clinical development (as a part of FDA’s critical path
initiative)
 Often take less than 6 months to complete.
 Reduce attrition at phase 1.

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Objectives :-
 To increase the chance of success on subsequent drug development process.
 To evaluate and select the best lead candidate from multiple preclinical candidates.
 To generate ‘human PK-PD relationship data’ for a drug prior to phase 1 testing.
 To confirm whether the mechanism of action defined in non-clinical models can be achieved in humans.
 To refine and validate a biomarker assay.
 To evaluate the effect of drugs on target by using human tissue.
 To evaluate a novel imaging probe in human by determining its distribution, binding properties and
effect on target.

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TYPES OF PHASE 0 STUDIES
PHARMACOKINETICS (PK) OR IMAGING :- Evaluate human bio distribution and target-
binding characteristics using sensitive imaging techniques and microdoses.
Preclinical toxicology studies should demonstrate that a dose 100 times of the
proposed human dose does not include adverse effects.
PHARMACOLOGICALLY RELEVENT DOSES :- Evaluate human PK of two or more analogues
to select a lead agent .
Preclinical toxicology studies must establish the NOAEL (No Observed
Adverse Effect Level) in a rodent 2week toxicology study.
PHARMACODYNAMIC END-POINT STUDIES :- Evaluate whether the new molecular
entity modulates its intended target.
Supporting preclinical toxicology studies are generally short-term, modified-
toxicity or safety studies in 2 two species. Dosing levels for these studies are not
specified.

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DESIGNING A MICRODOSING :-
There are several considerations that should be taken into account before initiating phase 0 trial.
Suitable candidates must fulfil some pre requisites like :
 Primarily PD end point is important for further development.
 Detectable or measurable and validated biomarker or target present.
 Have wide therapeutic window.
 Target or biomarker modulation occurs in microdose within 7 days.

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Procedures :- Drug candidate selected
Regulatory requirement
(14 day single dose animal toxicity study)
Exploratory INDA should be submitted
Microdose is calculated
Biomarker & bio analytical methods
Involves 10-15 healthy volunteer/patients
Limited duration of dosing (1-7 days)
Bioanalytical samples obtained (pre & post dosing )

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Number /duration of
doses
Maximum dose Preclinical requirements
Approach 1 1 Max 100 mcg & <1/100 of NOAEL or
<1/100 of pharmacological active dose.
14 days extended single
dose toxicity in rodent.
Approach 2 5 Each dose:100mcg<1/100 of NOAEL or
<1/100 of pharm active dose.
7 day repeated dose toxicity
in rodent.
Approach 3 1 Starting at sub therapeutic dose and
moving into the anticipated therapeutic
range but <1/2 NOAEL.
Extended single dose
toxicity in rodent and non
rodent.
Approach 4 Multiple, <14 days Starting dose <1/50 of NOAEL AUC; into
the anticipated therapeutic range but
<10th preclinical AUC if no toxicity, or
<NOAEL.
14-day repeated dose
toxicity in rodent and
non-rodent.
Approach 5 Multiple, <14 days Starting dose <1/50 NOAEL; into the
anticipated therapeutic range but
<non rodent NOAEL, or <1/2 rodent
NOAEL.
14-day repeated dose
toxicity in rodent and
non-rodent.

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Potential ethical barriers :-
• No diagnostic and/or therapeutic intent or benefit from phase
0 trial.
• Risk from research-related interventions, for instance repeated
tumour biopsies, biochemical analysis and CT scans, etc.
Proper informed consent process of phase 0 must include :
 Clear explanation of rationality of the study.
 Proper explanation that phase 0 is not a therapeutic trial rather an experimental
research.
 Absolutely no anticipated direct clinical benefit to the participant
Therefore, it is better to consult with and get approval of the institutional bioethics
committee prior to initiation of phase 0 clinical trials.
The necessary end points of phase 0 trials must be defined in real time so that
immediate treatment intervention can be given to the patients by multidisciplinary
investigators.

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ANALYTICAL METHODS

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Sensitive bio-analytical methods like
LC-MS
AMS
PET
are most commonly used tools for phase 0.
AMS(Accelerator Mass Spectrometry) is an ultrasensitive bioanalytical platform capable of
quantifying 14C-labelled compounds with attomole(10-18 ) sensitivity.
The exceptional sensitivity of AMS enables micro dosing studies performed at sub
pharmacological levels.
PET scan(Positron Emission Tomography) is another highly sensitive analytical platform
which is used for measuring extremely low quantities of drug in phase 0 micro dosing
studies.
-- useful for real time distribution, receptor occupancy and pharmacodynamic study.
For PET 15O ,11C , 13N, 124I type of radio-labelling is needed.

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AMS
(Accelerator Mass Spectrometer)
PET
(Positron Emission Tomography)

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MICRODOSING AND REGULATORY GUIDELINES :-
 Position paper from European Medicines Agency in 2004.
 Guidelines from the FDA in 2006.
 Guidelines from Japan in 2008.
 The ICH M3 International Guideline in 2009

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Advantages of Microdosing :-
 Reduce the cost and time of drug development.
 By rejecting the non-potential drug early in development phase, it reduces the unnecessary exposure of the
relatively large participants.
 Risk of adverse events is negligible.
 Can be done in vulnerable patients, such as women in reproductive age, cancer patients, renal impaired
patients, etc.
 Large scale multiple animal studies can be avoided for the non potential agents.
 Pre-clinical safety information for microdosing is very less (4-6 months for phase 0 Vs 12-18 months for
phase 1)
 During me-too drug development, comparative human microdose studies can be done.
 Improve the efficiency and success of subsequent trials, particularly for the development of molecularly
targeted agents.

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EMERGING USES OF MICRODOSING :-
 Measuring drug concentrations at the site of action and receptor occupancy by using
radioisotope.
 Detecting receptor modulation and biomarker.
 Obtaining drug clearance data by using an IV microdose.
 To identify primarily a potential drug delivery system for a candidate drug.
 To study drug-drug interactions.
 To study genetic polymorphisms using microdose.

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LIMITATIONS OF MICRODOSING :-
• Absence of therapeutic intent discourages the volunteers.
• Very few validated biomarkers are available for predicting the efficacy of some drugs
(anti-cancer activity).
• False negative results can lead to discontinuation of promising candidates.
• Developing radio isotope for analytical methods like AMS and PET are costly & needs
specialised mechanism.
• Nonlinear pharmacokinetics, if exists, can create problems in dose extrapolation.

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CONCLUSION
The aim of phase 0 is not to test the therapeutic effects but to
check that the drug behaves as expected in humans and to gather
preliminary data regarding what the drug does to the body & what
the body does the drug.
Phase 0 clinical trials are also used to rank candidate drugs &
select which ones should progress to phase 1 trials.
Therefore, this trial plays a crucial role in facilitating and
quickening the development of new drugs, especially in the field of
oncology.

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REFERENCES
• SK Gupta, New Drug Development, Drug Discovery and Clinical Research,1st edition, pg : 27 to 34.
• Vishal Bansal, Clinical Research Fundamentals & Practices, 1st edition, phases of clinical trials, chapter 3,
page no- 34 to 37.
• Sougata Sarkar, Vartika Srivastava, Manjushree Mohanty, Postgraduate Pharmacology, 1st edition,
phase0 trials/Microdosing, page no : 204 to 208
• Rituparna Maiti, Postgraduate Topics in Pharmacology, 3rd Edition, clinical trial:phases, chapter 1, page
no- 3 to5.

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