clinical trials 0-5

2. Overview
• History
• Definition
• Regulatory bodies
• In silico and in vitro trials
• Pre clinical trials
• Phases of clinical trials
• Types of clinical trials

3. History
• James Lind, Scottish physician
• First ever clinical trial
• Group of sailors – suffering
from Scurvy
• Vinegar to cider
• Citrus fruits
• Discovered Vitamin C can cure scurvy

4. Definition
• Clinical trials mean a systematic study of a new
drug ( therapy protocols, devices ) in human
subjects to generate data for discovering or
verifying the clinical claims or pharmacological
and adverse effects with an aim to determine
the safety and efficacy of drugs in question

5. Regulatory bodies
• U.S.A – Food and drug administration
• U.K – Committee on safety of medicine
• Japan – Ministry of health labor and welfare
• India – Drugs controller general, Govt.of India

6. FDA
 1906 – Interstate transport of adulterated
food and drugs
 1938 – Elixir sulfanilamide
 1960 – Thalidomide
Safety
Efficacy

7. Drug development steps

8. In silico
• Simulator software available
• Predict mechanism, metabolism, distribution
• Expected to contribute in reduction of animal
use
• Disadvantage: applicable only to those areas
which are well understood. Also hepatotoxicity
neurotoxicity can not be predicted

9. In vitro
• Isolated cells, tissues and organs
• The National disease research institute- 130
types of tissues for >50 types of disease
• E.g.: monoclonal antibodies – cultured cells
• Limitation: not available for all the tissues
Normal systemic pharmacokinetic
profile (ADME) is absent.

10. PRE CLINICAL
 Non human
• - Lab
• - Animal (rats, rabbits, etc.)
 Pharmacological studies: to know
 Biological activity
 Mechanism of action
 Selectivity and specificity
 Drug metabolism

11. • Toxicity – Acute toxicity
Sub acute toxicity
Chronic toxicity
Including effects on reproduction,
teratogenicity, carcinogenicity and
mutagenicity.

12. PHASES
 Phase 0: Pharmacodynamic (PD) and
pharmacokinetics (PK)
 Phase 1: Screening for safety
 Phase 2: Efficacy of the drug
 Phase 3: Final confirmation of safety and
efficacy
 Phase 4: Post marketing surveillance
 Phase 5: Translational research

14. • U.S FDA in 2006
• Speed up development of promising drugs
• Go / no go decision

15. Thalidomide
tests in pregnant
mice, rats, and
guinea pigs were
negative.
Cerivastatin
substantial risk for
severe or fatal
rhabdomyolysis.
16
Fenclofenac
No animal toxicity in
10 species. Severe
liver toxicity in
humans
Cisapride
Heart rhythm
disturbances in
trials, but not in
animal studies
5 2
34
Troglitazone
Safe in rats, severe
liver failure in
humans.
Phenylbutazone
Bone marrow toxicity,
phototox & liver tox
only in humans

16. Penicillin
Discovered in 1929
Not used till 1939
because of its
ineffectiveness in
curing infected rabbits
Furosemide
Experiments in
mice: extensive
liver damage
Aspirin
Causes teratogenic
malformation in mice,
rats, dogs, cats, rabbits
and monkeys

17. Phase 0 or microdose
• Microdosing :
• Less than 1/100th of the dose calculated to
yield a pharmacological effect of the test
substance based on primary
pharmacodynamic data obtained from in vitro
and in vivo (typically doses in or below the low
microgram range) and at a maximum dose of
<100microgram

18. Objectives of microdosing study
 To clarify bioavailability and PK profiles
 To clarify metabolic profiles
 To obtain information on tissue distribution
18

19. Basic features
 First-in-human trial conducted prior to
traditional Phase 1 study
 Small number of subjects (≈10-15)
 Limited drug exposure
 Low, non-toxic doses (<100mcg)
 Short duration (≈ ≤7 days)
 No therapeutic intent
 Eliminate bad agents early (rapid clearance,
poor bioavailability, fails to reach target)

20. Drug candidates (NME/NCEs)
Animal
modelsIn-vitroIn-silico
Limited toxicology studies
Human microdose study
(Phase 0)
PROCEDURE

21. • Plasma / urine / biopsy sample serially
collected
• Sample analyzed for parent drug and
metabolite
• Microdose -> micro plasma drug concentration
• Extremely sensitive analytical methods
required

22. 2
1
POSITRON EMISSION
TOMOGRAPHY (PET)
 Drug specific receptor ligand
labeled with a short lived
positron emitting isotope
 Distribution of drug and
relative concentration at
target area over time can be
visualized
 Info: mostly PD data through
real time imaging and limited
PK data

23. Liquid chromatography mass
spectrometry
 Generate drug concentration
data from samples(plasma/
urine) overtime.

24. Accelerator mass spectrometry
 AMS works on isotope ratio
method
 Measures total 14C content
 As well as 14 C content ratio
of parent drug to metabolite
after separation by HPLC
 Info: Extent of metabolism
measure of first pass effect

25. 10.
0
Oral microdose (100
ug)
1.
0
0.
1 0 1 2 3 4 5 6 7 8 9
Time
(h)
ng/mLper1mgdose
midazolam
Oral 7.5 mg dose midazolam
Parameter Oral dose
t½ 4.0 3.0
%F 22 23
0.1 mg 7.5 mg
PK prediction

26. Study in sensitive population
• Inherent low risk of toxicity: PK studies can be
undertaken

27. 34 82% were scalable
Orally
administe
red drugs
11 100% were
scalableIV administered
drugs
LITERATURE REVIEW
There are 45 drugs with data (in peered
reviewed literature ) comparing microdose PK
to therapeutic dose PK

28. PHASE 1
 Volunteers ( healthy and unhealthy) (10-100)
 Safety , tolerance
 Types
• - Single ascending dose studies
• - Multiple ascending dose studies
• - Food effect assessments

29. Single ascending dose studies
(SAD)
• SAD those in which small groups (3) of subjects are
given a single dose of the drug while they are
observed and tested for a period of time.
• If no adverse effects, dose is escalated with 3 new
healthy subjects
• If toxicity is observed then 3 more subjects are
given the same dose and if found toxic, the previous
dose is considered as max. tolerated dose (MTD).

30. Multiple ascending dose (MAD)
• MAD are conducted to understand the
pharmacokinetics and pharmacodynamics of
multiple doses of the drug.
• A group of patients receives multiple low doses of
the drug
• Samples (of blood, and other fluids) are collected at
various time points
How the drug is processed within the body- analyzed

31. Food effect studies
• Volunteers are given 2 identical doses of the drug
on different occasion, one while fasting and
another after being fed

32. PHASE 2
 First time in patients with target disease
 100-300 subjects
 Phase 2A (IIA)
• - Assess dosing requirements
 Phase 2B (IIB)
• - Study efficacy
 Study design – case series, RCT

34. PHASE 3
 Compare new treatments with the best
currently available treatment
- Confirms its effectiveness
- Monitor side effects
 Randomized controlled multicenter
trials
 Drug licensing studies (pre-marketing phase)
 Large study groups (300-3000 subjects)

35. • Phase IIIA
- conducted prior to regulatory submission
of a new drug application.
• Phase IIIB
- after submission, but before approval the
new drug.

36. PHASE 4
 Post marketing surveillance
 Safety surveillance
 Rare or long term adverse effects over a
much larger patient population
 Harmful effects discovered by phase IV
trials may result in a drug being no longer
sold, or restricted to certain rules.
• E.g.: Rofecoxib

37. Phase 5
• Used to signify the integration of a new clinical
treatment into widespread public health
• It is a survey without administration of drug
• Focus is to determine whether or not the
therapeutic effect is realized in day to day clinical
practice

38. • To seek additional marketing claims for
-new formulation
-new indication
-new combination
Some example
• Phenytoin sodium / lactose
• Phenytoin uses
• Methyldopa + diuretic combination

39. Basic features
• No dosing
• No patient monitoring
• Main focus – new therapy
• All reported use
• Research on data collected

40. Phases Dosing Number of
subjects
Main goal
0 Sub
therapeutic
About 10 PK and PD
IA/IB/IC Ascending
dose
20-100 Safety
IIA/IIB Therapeutic
dose
100-300 Efficacy
IIIA/IIIB Therapeutic
dose
300-3000 Therapeutic
use
IV Therapeutic
dose
Anyone
seeking
treatment
Long term
effect
V No dosing All reported
use
Research on
data collected

41. • Treatment Trials- test experimental treatments, new
combinations of drugs, or new approaches to surgery or
radiology/radiation therapy.
• Prevention Trials- look for better ways to prevent disease in
people who have never had them or prevent them from
returning.
• Diagnostic Trials- conducted to find better tests or procedures
for diagnosing a particular disease or condition.
• Screening Trials- test the best way to detect certain diseases or
health conditions.
• Quality of Life- explore ways to improve comfort and the
quality of life for individuals with chronic illness

42. THANK YOU