This document provides an overview of Phase 0 clinical trials, also known as microdosing trials. It discusses: 1. The concept of microdosing involves administering very low, subtherapeutic doses of new drug candidates to humans to obtain pharmacokinetic and pharmacodynamic data early in development. 2. Microdosing trials have several goals including predicting human pharmacokinetics better than animal models to facilitate candidate selection and eliminate unsuccessful compounds earlier. 3. The procedure involves collecting and analyzing plasma, urine or biopsy samples using sensitive techniques like PET scans and LC-MS to measure low drug concentrations. 4. Microdosing has potential applications in areas like predicting human pharmacokinetics,

1. Phase Zero
Chaithanya Malalur
Clinical trials
Smita Shenoy

2. Protocol
Introduction
Background and curent
scenario
Concept of MD
Basic features and goals.
Procedure & analysis
Dosing, sample collecting
and analysis
Application
Advantages, limitations
and literature review
Regulatory guidelines
FDA, EMA and Indian
perspective
Challenges
The road ahead.
2

3. 1.
Introduction
3

4. ‘’
Stagnation of
new drug discovery?
background
In introduction
of NMEs
Investment in
R&D
4

5. ‘’
NMEs per year -vs- R&D expenditure
background
NMEsperyear
TotalR&Dspentperyear(billionUS$)
NMEs
R&D spending 5

6. ‘’background
Single marketed drug
Favorable
PK
parameters
10-15 yrs
sustained
efforts
500 mil – 1
billion US$
6

7. IND failure – lets explore the reasons
fail phase 1 because
of PK/PD, safety or
efficacy issues
7
how reliable are they really?
Animal toxicity studies

8. Animal toxicity
How reliable
are they?
studies Thalidomide
tests in pregnant
mice, rats, and
guinea pigs were
negative.
1
2
Fenclofenac
No animal toxicity
in 10 species.
Severe liver
toxicity in humans
4
Troglitazone
Safe in rats,
severe liver failure
in humans.
3
Phenylbutazone
Bone marrow
toxicity, phototox &
liver tox only in
humans
6
Cerivastatin
substantial risk for
severe or fatal
rhabdomyolysis.
5
Cisapride
Heart rhythm
disturbances in
trials, but not in
animal studiesas many as 50% of FDA-approved drugs
are withdrawn or relabeled due to
unanticipated side effects in humans
8

9. Animal toxicity
How reliable are they?
studies
Penicillin Furosemide Aspirin
Discovered in 1929
Not used till 1939
because of its
ineffectiveness in
curing infected rabbits
Experiments in mice:
extensive liver
damage
Decades of clinical
use have proven its
safety for humans
Causes
teratogenic
malformations in
mice, rats, dogs,
cats, rabbits, and
monkeys
How many possibly life-saving drugs have been discarded
because of toxicities in other animal species?
9

10. Animal toxicity
How reliable are they?
studies
No correlation between humans and
animal Bioavailability for any species
that were examined (rodents, dogs,
primates)
Allometric scaling
- Review by Gram and Sinlow
10

11. Take a NME to phase 1 faster
Need of a methodology which will
11
Reduce failure in late developmental
stages by predicting PK/PD and
bioavailability in humans better

12. 2.
Concept of
microdosing

13. Concept of microdose
Microdose (MD)
<100 μg dose of a drug that can be
administered as a single dose or
divided doses in any subject.
MD study
 Exploratory study
 early phase-1
 limited human exposure
 no therapeutic intent
 not intended to examine clinical
tolerability
- ICH M3 Regulatory Guideline
13

14. ‘’ Safely administering sub pharmacological
doses of NCEs/NMEs to humans to obtain
PK/PD, bioavailability and metabolism at much
earlier stage
principle
14

15. Principle of
micro-dosing
“best model for man is man”
DoseExtrapolation
Extrapolation
Species
15

16. ‘’Basicfeatures
First in human trial (prior to traditional phase 1)
Small number of subjects (10-15)
Limited exposure to drug
- Low non-toxic dose
- short duration (</= 7 days)
No therapeutic intent (clinical benefit)
16

17. ‘’ Provide PK-PD data prior to definitive
testing in phase 1
Evaluate BA to select most promising
dose
Eliminate bad agents early (fails to reach
target, rapid clearance, poor BA)
goals
17

18. 3.
Procedure

19. ‘’Procedure
Drug candidates (NME/NCEs)
In-silico In-vitro
Animal
models
Limited toxicology studies
Human microdose study
(Phase 0)
19

20. ‘’Analyticalmethod
Plasma /urine /biopsy sample serially collected
Samples analyzed for parent drug and metabolites
Micro-doses → micro plasma drug concentrations:
extremely sensitive analytical methods required
- PET (Positron Emission Tomography)
- LC-MS (Liquid Chromatography – Mass
Spectrometry)
- AMS (Accelerated Mass Spectromerty)
20

21. PET – Positron Emisson Tomography
Drugs/specific receptor ligand
labelled with a short lived
positron emiting isotope
Distribution of drug and relative
concentration at target area over
time can be visualised
Info: mostly PD data through real
time imaging and limited PK data
21

22. LC-MS
Generate drug concentration data
from samples (plasma / urine)
over time
22

23. LC-MS with AMS
AMS works on isotope ratio method
Measures total 14C content
As well as 14C content ratio of parent drug
to metabolite(s) after separation by HPLC
Info:
- extent of metabolism
- measure of first pass effect
Sensitivity: 10-100 pg/ml (1pg/ml)
can detect in femto-molar range
23

24. 4.
Application

25. Where is MD headed?
Primary emphasis: early PK prediction
Estimating drug conc. at site of action
Metabolic profiling of drug
Drug-drug interactions
Study in vulnerable population
25

26. ‘’PKprediction
0.1
1.0
10.0
0 1 2 3 4 5 6 7 8 9
Time (h)
ng/mLper1mgdose
Oral microdose (100 ug)
midazolam
Oral 7.5 mg dose
midazolam
Parameter Oral dose
0.1 mg 7.5 mg
t½ 4.0 3.0
%F 22 23
26

27. Estimating drug conc. at site of action
Blood (and cells)
Lymph
Cerebrospinal fluid (CSF)
Synovial fluid
Biopsy
Broncho alveolar lavage
Bile
Saliva, tears and nasal tissue
Hair follicles
Tumor (during surgery)
Measuring active drug
at the site of action gives a much
improved correlation to efficacy
27

28. Metabolic profiling of a drug
Samples collected following microdosing, can be used to metabolically
profile a drug using PET and LC-MS/ AMS
28
% of drug metabolism
in liver
% of drug metabolism
in kidneys
% of drug metabolism
in plasma

29. Drug-drug interactions
Developmental drug is administered as a micro-dose before and after
administration of pharmacologically active doses of inducer and/or inhibitor
PK parameters compared for before and after – gives an idea of DDIs
29

30. Study in sensitive populations
Inherent low risk of toxicity: PK studies can be ethically undertaken in
Potential to compare healthy metabolism with
metabolism in diseased states
30

31. ‘’advantages
Early selection of promising compounds
Avoid unnecessary exposure of participant to
not-so-promising compounds
Early elimination of not-so-promising compounds
– saves resources
Pose less risk of overall human toxicity (low dose
/ less duration / limited subjects)
31

32. ‘’advantages
Lesser preclinical safety package required –
reduce animal use
Drug can be ethically tested in sensitive
population
Establishes likely pharmaceutical dose more
accurately for subsequent Phase 1 study
Overall acceleration of drug development process
32

33. ‘’limitations
Not enough studies to prove
false negatives (good compound rejected)
false positives (unsuitable compounds)
Cautiously interpret while using drugs with
non-linear / complex kinetics
Few drugs dissolve readily at low doses but
have limited solubility at high dose
Lack of therapeutic intent
Requires expensive equipment
33

34. Literature review
There are 44 drugs with data (in peered reviewed literature)
comparing microdose PK to therapeutic dose PK
34
11
Orally
administered
drugs
IV administered
drugs
82% were scalable
100% were scalable
34

35. Published human micro-dose trials
CREAM Trial
(Lappin et al (2006) Clin Pharmacol Ther 80, 203-215)
EUMAPP
(Lappin, et al (2010) Eur J Pharm Sci 40, 125–131)
(Lappin et al (2011) Eur J Pharm Sci 43, 141-150)
NEDO
(Yamane et al 2009 Drug Metab pharmacokinet 2009; 24(4): 389-403.)
(Tozuka et al 2010, Clin Pharmacol Ther 2010; 88(6): 824-30.)
(Yamazaki et al (2010), J Clin Pharm Ther 2010; 35(2): 169-75)
35

36. 5.
Regulatory
guidelines

37. Regulatory guidelines – global
Position Paper on
Non-clinical Safety
Studies to Support
Clinical Trials with a
Single Microdose
(23 June, 2004)
Guidance for
Industry
Investigators and
Reviewers.
Exploratory IND
Studies (2006) “CPI”
Guidance on non-
clinical safety
pharmacology
studies for human
pharmaceuticals
(December 2009)
37

38. Indian regulatory
perspective
ICSR Proposed change in regulation to
permit microdosing studies in India
2007-08
DTAB Unanimously approved and
proposed further amendments
GovernmentDisregarded due to nontechnical
sensitivities surrounding clinical research
38

39. 6.
Challenges

40. Challenges – the road ahead
There is a need for scientifically
validating microdosing studies
in the field of drug development
Ultimately to benefit patient,
reduce animal use and give a
boost to pharma industry
40

41. Conclusion
Tread lightly

42. The difficulty lies, not in the
new ideas, but in escaping
from the old ones
John Maynard Keynes

43. References
 Lappin, G., & Garner, R. C. (2008). The utility of microdosing over the past 5 years.
 Rani, P. U., & Naidu, M. U. R. (2008). Phase 0-Microdosing strategy in clinical trials. Indian
journal of pharmacology, 40(6), 240.
 Shanks, N., Greek, R., & Greek, J. (2009). Are animal models predictive for
humans?. Philosophy, Ethics, and Humanities in Medicine, 4(1), 2.
 Hayden, E. C. (2014). Misleading mouse studies waste medical resources.Nature.
 Pippin, J. J., & Stoick, K. (2005). Dangerous Medicine: Examples of Animal-Based “Safety” Tests
Gone Wrong. Retrieved October, 6, 2009.
43

44. References
▣LoRusso, P. M. (2009). Phase 0 clinical trials: an answer to drug development stagnation?. Journal
of Clinical Oncology, 27(16), 2586-2588.
▣Kummar, S., & Doroshow, J. H. (2011). Phase 0 trials: expediting the development of
chemoprevention agents. Cancer Prevention Research, 4(3), 288-292.
▣Bhandari, P. R. (2013). Phase 0 trials (microdosing): A new paradigm in clinical
research. International Journal of Health & Allied Sciences, 2(2), 75.
▣GUIDANCE, D. (2005). Guidance for Industry, Investigators, and Reviewers Exploratory IND
Studies. Center for Drug Evaluation and Research (CDER).
44

45. References
▣Vijayaraghavan, R., & Ramesh Kumar, G. (2010). Impact of phase zero trials (micro-dosing) in
clinical trial research. Int J Appl Biol Pharm Tech, 2, 486-90.
▣Seth, S. D., Kumar, N. K., & Dua, P. (2009). Human microdosing; a boon or a bane?. The Indian
journal of medical research, 130(2), 202-204.
▣Bergström, M., Grahnen, A., & Långström, B. (2003). Positron emission tomography microdosing: a
new concept with application in tracer and early clinical drug development. European journal of
clinical pharmacology, 59(5-6), 357-366.
45

46. Thank you