This document discusses phase 0 clinical trials, also known as microdosing studies. Phase 0 trials involve administering very low, non-therapeutic doses of an experimental drug to small groups of subjects to obtain preliminary pharmacokinetic and pharmacodynamic data before proceeding to full phase 1 trials. The goals are to accelerate drug development, eliminate unsuitable drug candidates early to save costs and reduce unnecessary risk to subjects and use of animals in testing. Regulatory guidelines have been established for microdosing studies. While microdosing offers benefits, limitations include potential for false predictions and difficulty motivating subject participation due to lack of intended therapeutic benefit. Ethical considerations also need to be addressed for these early-stage trials.

1. Phase 0 Clinical trial
Dr. Satyabrata sahoo
DM Resident Clinical Pharmacology
Dept. of Clin.& expt. Pharmacology
School of Tropical Medicine, Kolkata

2. Contents
• Introduction
• Drug development Process
• Concept Phase 0
• Basic features and goals
• Regulatory guidelines
• Uses of phase o
• Advantages and limitations
• Ethical considerations
• Indian scenarios
• Challenges
• conclusion

3. Introduction
• Drug development is a long, complex and expensive
activity
• Requires 10-15 years of sustained efforts
• Cost of US $ 500 million to $ 1 billion for a single
marketed drug
• Surveys over the past 10 years- research and drug
discovery expenditure is increasing almost
exponentially year and year.
• Nearly one-third of the investigational new drugs(INDs)
fail in the phase 1 trials, many due to PK/PD, safety or
efficacy issues

4. Cont..
• If the phase 1 failed, then the human volunteers
would have been unnecessarily exposed to a failed
drug and large numbers of animals would have
been used.
• Thus phase 0 or micro dosing studies introduced to
address issues pertaining to drug metabolism and
pharmacokinetics.
• It offers a way of developing drugs in a faster ,more
cost effective and ethical way than ever before

5. Drug development Process

8. Concept of Phase 0
• The concept of phase 0/micro dosing first appeared in 1990s
as a method of assessing human pharmacokinetics prior to
full phase I clinical trials and the first data appeared in the
literature in 2003( Garmer RC, Lappin G)
• Study of new drugs in micro doses to derive PK information in
human before undertaking phase I studies is called phase 0
• Microdose: less than 1/100 of the dose of a test substance
calcuated to produce pharmacological effect with a max dose
≤ 100 micrograms
• Objective: To obtain preliminary pharmacokinetic data
• Micro dosing approach could accelerate drug development
without compromising clinical safety
• Micro dosing helps researchers select better drug candidates
for clinical trials by providing early human PK and
bioavailability data.

9. Basic features of phase 0 trials
• First-in-human trial conducted prior to traditional
phase 1 study
• Small number of subjects(10-15)
• Limited drug exposure
Low, non-toxic doses
Short duration(≤7 days)
One course only
• No therapeutic intent(clinical benefit)
• Phase 0 trials are not definitive studies(further
studies are required)

10. Various Goals of Phase 0 trial
• Provide human PK-PD relationship data prior to
defintitive phase 1 testing
• Evaluate human PK(e.g. Bioavailability) to select
most promising candidate for further development
• Eliminating bad agents early in clinical development
because of poor PK or PD properties
• E.g. Lack of target effect, poor bioavailability,very
rapid clearance

11. Microdosing and Regulatory Guidelines
• EMEA position paper on Non clinical safety studies
to support clinical trials with a single microdose
• FDA Us departmental of Health and Human services
guidance for industry investigators and reviewers
• ICH Topic M3 note for guidance on nonclinical
safety pharmacology studies for human
pharmaceuticals
• The microdose of drug defined by the USFDA is
analogous to that defined by EMEA
• The latest ICH M3 guideline now universally
accepted.

12. Uses of phase 0
• PK-PD
• Drug drug interactions
• Measuring drug concentration at site of action
• Metabolic profiling
• Study in vulnerable populations

13. Advantages
• Early selection of promising compounds
• Overall acceleration in the process of drug
development
• Avoid unnecessary exposure of the participants to
the not so promising compounds
• Not so promising compounds can be eliminated
earlier thereby saving costs
• Less number of animals used

14. Limitations
• It may lead to false positive or false negative results
• Caution needs to be exercised while applying this
methodology to the drugs showing complex/nonlinear
kinetics
• Since certain drugs dissolve readily at low doses but
exhibit limited solubility at higher doses, it may be
difficult to predict the absorption characteristics at the
microdose levels
• There is lack of any therapeutic and/or diagnostic
intent
• Difficult to motivate the volunteers to become a part of
the trial
• The database for microdosing study is very small

15. Ethical considerations
• Since Phase 0 trials will definitely not benefit the enrolled person, convincing
to participate in phase 0 trial is difficult
• Indeed, Phase 0 trials are both ethically challenged and ethically
challenging.
• The issue of being ethically challenged can be overcome with scientifically
valid and rigorous methodology

16. Indian Scenarios
• In 2007-2008 the ISCR proposed a change in
regulation and permit phase 0 trial in India
• Regulatory change enabling phase 1 and
microdosing studies open the door for early clinical
development
• This could bring India in to the main stream of
pharmaceutical research

17. Microdosing Studies: Challenges
• Failure to recognize the potential benefits of
microdose studies
• Human microdosing is a promising strategy
• Despite obstacles in terms of infrastructure, existing
regulations and ethical challenges, the issue is
worth considering

18. Conclusion
• Human microdosing holds significant promise as an
analytical tool
• Microdosing may help both patients and
pharmaceutical industry.
• Helps to determine the first dose for the
subsequent phase I clinical studies

19. References
1.Shivaani Kummar, MD*, Larry Rubinstein Cancer J. 2008 ; 14(3): 133–
137. doi:10.1097/PPO.0b013e318172d6f3.
2. James H Doroshow, Future Med,Chem(2009) 1(8)
3.FDA.gov.in
4.Lappin G & Gramer,R.C.(2008)The utility of microdosing over the past
5 years

20. THANK YOU