Clinical trials are conducted in phases to evaluate the safety and efficacy of new medical interventions in humans. Phase I trials involve small groups of subjects and focus on safety, tolerability and dosing of new drugs. Phase II trials involve larger groups of patients and aim to establish effectiveness and optimal dosing. Phase III trials involve thousands of subjects and compare the new medical intervention to the current standard of care or placebo under blinded conditions. The results of phase III trials are required for regulatory approval prior to widespread use and administration of the new medical intervention.

1. Dr. Dhruva Kumar Sharma
Department of Pharmacology
SMU/SMIMS
Saturday, the 23rd Of Aug, 2014

2. Clinical Trials: Phases And Types
2

3. Protocol:
• Definition
• Aims and Objectives
• History
• Drug development process and Phases
• CRO
• Phases of clinical Trials
• Types of clinical trials
3

4. • Clinical trials are prospective biomedical or
behavioral research studies on human
subjects that are designed to answer
specific questions about biomedical or
behavioral interventions (novel vaccines,
drugs, treatments, devices or new ways of
using known interventions), generating
safety and efficacy data
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5. AIMS AND OBJECTIVES OF
PERFORMING CLINICAL TRIALS
● Discovering and confirming the role of new
drugs for the future pharmacotherapy of
mankind as a whole
● To evaluate safety and efficacy of
experimental drug relative to its adverse
drug reactions both in healthy volunteers
and concerned patients
● Licensure process of a new drug

6. A short history of the clinical trial-562BC
• The evolution of clinical research traverses
a long and fascinating journey
• The first documented experiment
resembling a clinical trial - military leader
“King Nebuchadnezzar”
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7. • The experiment looked at two groups who
either partook of “the King’s meat” and
wine at the royal table, or did not
(vegetables and water only), over a trial
period of ten days
• After ten days, the “vegetables and water
group” looked healthier and much more
physically fit
7

8. • Not exactly a randomized, double-
blinded, placebo-controlled clinical
trial, but the modest experiment may
have been one of the first times in
human history that a medical test,
however rudimentary, guided a
decision about public health
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9. • In 1747: One of the most famous clinical
trials was James Lind's demonstration
that citrus fruits cure scurvy
• He compares the effects of various acidic
substances, ranging from vinegar to cider,
on groups of afflicted sailors
• His study concluded that within six days,
the group who were given oranges and
lemons had largely recovered from scurvy
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10. International clinical trials day:
20th May
• International clinical trials day is
celebrated on 20th May
• In 1862/1906: FDA was founded
• In 1863: Concept of a Placebo was first
introduced in the world of clinical trials
• In 1923: Concept of randomization
• In 1943: The UK Medical Research
Council’s (MRC) trial to treat the common
cold is the first double blind controlled
study 10

11. • In 1947: The Nuremberg Code
• In 1964: The Declaration of Helsinki was
developed to establish a code of ethics
• In 1990: The International Conference on
Harmonization (ICH) was established
• Also In 1996: ICH/GCP guidelines
• In 2000: The Common Technical Document (CTD)
standard is established, creating a single
standard for the presentation of information to
regulatory agencies in the EU, USA and Japan
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13. Drug development process: 3 phases
1. DRUG DISCOVERY PHASE:
-During which the candidate molecules are chosen on
the basis of their pharmacological properties
2. PRECLINICAL PHASE:
-During which a wide range of animal studies are
performed, e.g., pharmacokinetic, pharmacodynamic
and toxicity studies
3. CLINICAL TRIAL PHASE:
-During which the lead compound is evaluated for
efficacy, safety, and adverse effects in human
volunteers and patients

14. Pre-clinical evaluation phase (Animal
studies)
• Wide range of animals studies are performed
• Involves screening, evaluation, pharmacokinetics
and short-term toxicity in animals
• The aim during this phase of development is to
satisfy all the requirements that are needed
before a compound is considered fit to be tested
for first time in humans
• Pre-clinical phase usually require – 2 to 4 yrs. for
completion

15. Pre-clinical evaluation phase
The major areas are-
• Pharmacodynamic studies
• Toxicological studies
• Pharmacokinetic studies
• Assessment of safety index

16. TOXICOLOGICAL STUDIES-
• The aim is to determine safety of the
compound in at least two animals species
(rat & dog) by oral or parenteral routes
a) Acute toxicity-
- single doses /small groups of animals
observed for overt effects and mortality
for 1-3 days.
- LD 50 is calculated

17. SUB-ACUTE TOXICITY-
• Identify target organs susceptible to drugs
toxicity
• Three doses are used on two animal species
• Animals maintained at the max. tolerated
doses for a minimum period of 4 weeks to a
max. period of 3 months
• Finally ,the animals are killed and subjected to
histopathological examination.

18. Chronic toxicity-
• Goals are same as for sub-acute toxicity.
Usually two animal species (one rodent and one non-rodent)
Duration- 1-2 years
May run simultaneously with clinical trials
Special toxicity-
• Effects on reproductive performance
• Teratogenicity
• Carcinogenicity
• Mutagenicity
• Local toxicity

19. • When the new drug passes the pre-clinical
pharmacological screening, the manufacturer
may file a
‘Preclinical New Drug’
Or
‘Investigational New Drug’ (IND)
application to an authorized drug control body of
the respective country
• In UK- CSM (Committee on Safety of Medicine)
• In USA- FDA (Food and Drug administration)
• In INDIA- Drugs Controller General, Govt. of India,
New Delhi

20. • The IND application must contain the
following information about the test drug in
question-
1. The chemical structure, source,
manufacturing data with details of its purity.
2. The preclinical data about
pharmacodynamics, pharmacokinetics and
toxicological studies with ED50 and LD50 data.

21. 3. Specifications of the dosage forms in
which it has to be administered to the
human beings.
4. A detailed description of the
investigational protocol to be undertaken
(including the dose and route of
administration )
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22. 5. The names and qualifications of each
investigator and the facilities available to
them
6. An agreement from the sponsors to submit
annual progress report regularly
7. A certification that “informed consent” will be
obtained from human volunteers and that
‘Ethics of research of human beings’ will be
strictly followed

23. • Clinical trials are conducted only after
satisfactory information has been gathered
that satisfies health authority/ethics
committee
• Depending on product type and development
stage, investigators initially enrol volunteers
and/or patients into small pilot studies, and
subsequently conduct progressively larger
scale comparative studies
23

24. • As positive safety and efficacy data are
gathered, the number of patients typically
increases
• Clinical trials can vary in size, and can
involve a single research entity in one
country or multiple entities in multiple
countries
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25. • Hence, a full series of trials may cost
hundreds of million dollars
• The burden of paying is usually borne by
the sponsor, which may be a
 governmental organization
 Pharmaceutical industry
 Biotechnology
 medical device company
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26. CRO
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• A contract research organization (CRO) is an
organization that provides support to
the pharmaceutical, biotechnology, and medical
device industries in the form of research
services outsourced on a contract basis
• A CRO may provide such services as
biopharmaceutical development, biologic assay
development, commercialization, preclinical
research, clinical research, clinical trials
management, and pharmacovigilance

27. • Many CROs specifically provide clinical-
study and clinical-trial support for drugs
and/or medical devices
• CROs range from large, international full-
service organizations to small, niche
specialty groups
27

28. • CROs that specialize in clinical-trials services can
offer their clients the expertise of moving a new
drug or device from its conception
to FDA marketing approval, without the drug
sponsor having to maintain a staff for these
services
• There are over 1,100 CROs in the world
• The largest CROs, according to Industry Standard
Research, are Quintiles, Parexel, Covance, Pharm
aceutical Product Development (PPD), Icon, INC
Research, and inVentiv Health Clinical
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29. • With regulatory approval, human testing
may then go forward (usually in three
phases)
• Drug is formulated into a suitable dosage
form and clinical trials are conducted in a
“LOGICAL PHASED MANNER”
• A fourth phase of data gathering and
safety monitoring is becoming increasingly
important and follows after approval for
marketing

30. • Once approved, the great majority of drugs
become available for use by any appropriately
licensed practitioner
• Highly toxic drugs that are nevertheless
considered valuable in lethal diseases may be
approved for restricted use by practitioners
who have undergone special training in their
use and who maintain detailed records

31. • Enormous costs: $150 million to several
billion, are involved in the development of
a single new drug that reaches the
marketplace
• Less than one third of the drugs tested in
clinical trials reach the market place
• Only 2 of 10 marketed drugs return their
research and development (R&D)
investments, thus providing considerable
motivation to develop “blockbuster drugs”

32. • Increasing regulatory challenges and litigation
resulting from real or suspected drug toxicity
after approval further increase the cost of
developing new drugs
• Unfortunately, only 10–15% of the new drugs
that achieve marketing approval represent
significant advances in safety and
effectiveness
• The remainder are merely molecular variants
(“me-too drugs”) on true breakthrough drugs

33. Clinical Trials: IND (for Phase I,II,III)
Ethical Considerations
• In each of the three formal phases of clinical
trials, volunteers or patients must be
informed of the investigational status of the
drug as well as the possible risks and must be
allowed to decline or to consent to participate
and receive the drug

34. PHASES OF CLINICAL TRIALS
Conventionally there are four phases of
clinical trials :
Phase I Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
Phase IV Clinical Trials

35. Additions :
Phase 0 – Microdosing Stategy
Phase V Clinical Trials – mainly an extension of
Phase IV Clinical Trials.

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37. PHASE I : Clinical Pharmacology and
Toxicity
● Carried out by qualified clinical
pharmacologists/trained physicians
● Non Blind or Open lable trials
● Total number of subjects : 25-100; Time
Required : 6 months - 1 year
● The drug is tested in normal healthy
volunteers (extremes of ages; elderly and children are
excluded)
● Phase 1 trials for cancer and anti-HIV drugs
are done in patients.

38. Objectives Of Phase I Clinical Trials :
1. To check for :
Safety
Tolerability
2. To determine whether human and animals
show significant pharmacokinectic
differences
3. To determine a safe clinical dosage range in
humans

39. For safe clinical dosage range
Begin with 1/5th or 1/10th the maximum tolerated dose
(mg/kg) in animals and calculate it for an average
human body weight of 70 kg.
The drug is then given in small increments till
therapeutically effective dose is obtained.
4. To determine pharmacokinetics of the
drug in humans.
5. To detect any predictable toxicity
There are different kinds of Phase I trial

40. SAD - Single Ascending Dose studies
● Features :
● - small groups of subjects are given a single
dose of the drug
● - they are observed and tested for a period
of time

41. ● No adverse effects observed, the dose is
escalated, and a new group of subjects are
then given a higher dose than previous
group
● This is continued until intolerable side
effects or adverse effects start showing up
[at which point the drug is said to have
reached the Maximum tolerated dose
(MTD)].

42. 2) MAD - Multiple Ascending Dose
studies
Features -
To understand better the pharmacokinetics &
pharmacodynamics of multiple doses of the
drug
A group of patients receives multiple low doses
of the drug, while samples are collected at
various time points and analyzed to acquire
information on how the drug is processed within
the body. The dose is subsequently escalated for
further groups, up to a predetermined level.

43. 3) Food effect
A short trial designed to investigate any
differences in absorption of the drug by the
body, caused by eating before the drug is
given
● These studies are usually run as a crossover
study, with volunteers being given two
identical doses of the drug while fasted, and
after being fed

44. Phase II trials
Or
Safety and efficacy (SE) trials
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45. Phase II : Therapeutic Exploration and
Dose Ranging
● Conducted by Physicians who are trained as
Clinical Investigators
● Last an average of 2 years.
● Number of subjects: 100-400; Volunteer
patients, selected according to specific
inclusion and exclusion criteria
● Multicentered Randomised controlled Trials
of the new drug is undertaken

46. Obective:
To Estabilish -
- Final formulation
- Dose of the drug
-Statistical End Points that represent
the targeted favourable outcome of
the study

47. End points may be:
a) Definitive End Point – which measures the
drug effect directly
b) Surrogate End Point – which is
predictive of the definitive end point
Phase II Clinical Trials are divided into
EARLY and LATE PHASES

48. EARLY PHASE II
[Establish Dose range]
● Usually a Randomised Single Blind Design
● A small number of patients upto 200
● Potential therapeutic benefits, side effects
and adverse effects are observed
● Main obejective – to estabilish a dose range
for more definitive trials to be undertaken in
the next late phase here

49. Late Phase II
[Efficacy]
● Randomized Double Blind Design
● Larger number of patients: 200-400
● Specifically designed to study efficacy (how
well the drug wroks at prescribed doses)

50. Types Of Study Design
50
ANALYTIC DESCRIPTIVE
EXPERIMENTAL NON EXPERIMENTAL
Randomised
Clinical Trial
Non
Randomised
Clinical Trial
Community
Survey
Case-
Control
Cross
sectional
Case-
Cohort
Cohort

51. Randomized Controlled
Trials

52. Avoidance of bias
• Use of a control group
• Blindness
• Randomization

53. Randomization: Meaning
• Not a random sampling
• Random allocation
– Cannot predict the treatment to be given
whether Active treatment or Placebo
• Eliminates selection bias

54. Randomization
• We want to assign a group of subjects to
one of two groups—Treatment A or
Treatment B
– How can we do this in a random manner?

55. Randomization
Random assignment
• Flip a coin
– “Heads”—Tx A
– “Tails”—Tx B

56. Randomization
Random assignment
• Roll a six-sided dice
– Even number—Tx A
– Odd number—Tx B

57. Randomization
Random assignment
• Table of random numbers
• Computer generated list

58. Random assignments
Random assignment
• Alphabetical
– Tx A = patients with last name A–M
– Tx B = patients with last name N–Z
• Telephone number/social security number
– Tx A = last digit odd
– Tx B = last digit even
• Sequential
– Tx A = morning patients
– Tx B = afternoon patients
• Bed number
– Tx A = odd bed number
– Tx B = even bed number

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•UNBLINDED, OPEN TRIAL
•SINGLE BLIND
•DOUBLE BLIND
•TRIPLE BLIND
BLINDING
Double-Blinded Single-Blinded

61. • Open Trial:
- both the researcher and the subject knows
the full detail of the treatment
Blind Trials:
• Method of “control experimentation”
• One / both parties are not informed of the
treatment being given
• Reduces bias arising from the treatment
knowledge
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62. Reduces bias like
• Recruitment and treatment allocation
• Patient care
• Attitudes of patients to treatments
• Assessment of endpoints
• Handling of discontinuations
• Exclusion of data from the analysis
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63. • Single-Blind Trial (Subject is blinded)
• Bouble Blind Trial (Investigator + Subject are Blinded)
• Triple-blind trial (Researcher + Investigator + subject
are blinded)
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64. Phase III Trials
Or
Comparative Efficacy Trials
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65. Phase III : Therapeutic confirmation /
comparison
● Large Scale Multicentred (heterogenous
population) randomised double blind study,
carried out by several physicians.
● Number of patients – 1000 – 5000 plus.
● Lasts an average of 5 – 6 years.
● Further estabilish safety and efficacy and
possible drug and food interactions.

66. ● Designed to verify the efficacy of the new
drug with the current 'gold standard'
treatment; and to minimise errors in the
information gathered in Phase I and Phase II
trials.
● Therefore these trials are made using
DOUBLE BLIND CROSSOVER STUDIES
● Most expensive, time-consuming and
difficult trials to design and run

67. ● At the end of the trial – Statistical analysis of
data is performed to determine the
significance of the results
● P-value of < 0.5% is taken as significant

68. New Drug Application
● On satisfactory completion of Phase III trials
a 'New Drug Application' is filed with the
Drug Control Authorities of the country
● It contains :
- Complete detailed monograph of the
product including information about dose,
dosage forms, dosage schedule, routes of
drug administration, side effects, adverse
effects

69. - Results of the trials
- Proposed registered name of the product
- Package insert
● If documentation is acceptable and is in
compliance with the regulations, the drug
control authorities can allow the drug to
enter the market with 'New Drug Status'

70. Phase IV : Post Marketing
Surveillance/studies
● It is the post licensing phase
● No fixed duration
● Performance of the drug is monitored for
several years
● After the drug has been marketed for
general use, data is collected on a pre
structured proforma about the efficacy,
acceptibility and adverse effects

71. • Data obtained from general practioners
and physicians of both hospital and private
set up
• Data is collected to discover any
rare/unique side effects or adverse effects;
or previously unknown therapeutic
benefits of the drug / its active metabolite
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72. ● It is a global report
● During the 'New Drug Status' period the
manufacturer is supposed to report any new
information about the drug concerning its
safety
● Periodic Safety update Report (PSUR) is to
be submitted every 6 months for first 2
years and then annually for the next 2 years

73. ● Further therapeutic trials involving special
groups like children, elderly, pregnant
/lactating women, patients with renal/hepatic
disease, etc. (which are generally excluded
during clinical trials) may be undertaken at
this stage
● Modified release dosage forms, additional
routes of administration, fixed dose drug
combinations, etc. may be explored

74. Phase 0 : Micro Dosing Strategy in
Clinical Trials
● New strategy to reduce the cost and time of
the drug developement process
● These are designed to speed up the
development of promising drugs or imaging
agents by establishing very early on whether
the drug or agent behaves in human
subjects as was expected from preclinical
studies
● Duration – 4-6 months

75. ● Involves administration of single subtherapeutic
doses(< 1/100th of the dose) of the study drug to a
small number of healthy volunteers (10 to 15) and
pharmacokinetics is worked out using highly
sophisticated instrumentation, such as Accelerator
mass spectrometry with radiolabelled drug, LC tandem
mass spectrometry to measure ultra low dose levels
● Primary goal – to inform decision making regarding
further development of relevant compounds

76. ● Knowing the pharmacokinetics of the drug
can also help in selection of the ideal
candidates for the study
● Especially important for oncology , as
anticancer drugs are therapeutically toxic,
and microdosing studies are therefore more
helpful here to decide the appropriate drug
to be studied
● May reduce overall cost of clinical trials

77. Limitations of Phase 0 Clinical Trials
● Gives no data on safety or efficacy
● By definition a dose too low to cause any
therapeutic effect
● But questions still have been raised by
experts about whether Phase 0 trials are
useful, ethically acceptable, feasible, speed
up the drug development process or save
money, and whether there is room for
improvement

78. Phase V Clinical Trials
● Extension of Phase IV Clinical trials
● Phase V is a growing term used in the
literature of translational research
● It refers to comparative effectiveness
research and community-based research
● It is used to signify the integration of a new
clinical treatment into widespread public
health practice

79. Types Of Clinical Trials
• Cancer clinical trials differ according
to their primary purpose
• They include the following types:
– Treatment. These trials test the
effectiveness of new treatments or new
ways of using current treatments in
people who have cancer
80

80. • The treatments tested may include new
drugs or new combinations of currently
used drugs, new surgery or radiation
therapy techniques, and vaccines or other
treatments that stimulate a
person’s immune system to fight cancer
• Combinations of different treatment types
may also be tested in these trials
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81. • Prevention: These trials test new
interventions that may lower the risk of
developing certain types of cancer
• Most cancer prevention trials involve
people who have a higher than average
risk of developing a specific type of cancer
82

82. • Some cancer prevention trials involve
people who have had cancer in the past;
these trials test interventions that may
help prevent the return (recurrence) of the
original cancer or reduce the chance of
developing a new type of cancer
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83. • Screening: These trials test new ways of
finding cancer early
• Cancer screening trials usually involve
people who do not have any signs or
symptoms of cancer but have a higher than
average risk of developing a certain type of
cancer because they have a family history
or history of exposure to cancer-causing
substances (e.g., cigarette smoke).
84

84. • Diagnostic. These trials study new tests or
procedures that may help identify, or
diagnose, cancer more accurately
• Diagnostic trials usually involve people
who have some signs or symptoms of
cancer
85

85. • Quality of life or supportive care: These
trials focus on the comfort and quality of
life of cancer patients and cancer survivors
• New ways to decrease the number or
severity of side effects of cancer or its
treatment
• How a specific type of cancer or its
treatment affects a person’s everyday life
may also be studied
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86. Sibling Clinical Trial
• This study will examine families in which
one sibling of a sibling pair, or twin pair,
has developed a systemic rheumatic
disease and one has not, to see if and how
the two differ in the following:
• Blood cell metabolism
• Types of cells in the blood
• Environmental exposures or genetic
factors that might explain why one
developed disease and the other did not
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87. • Families in which one sibling has
developed a systemic rheumatic disease,
rheumatoid arthritis, systemic lupus
erythematosus, scleroderma,
dermatomyositis, or myositis, and the
other has not, are eligible for this study
88

88. • The siblings may or may not be twins,
but must be of the same gender and
be within a 3-year age difference
• Biological parents, or, in some cases,
children, will also be included in the
study
• Normal, healthy volunteers will serve
as control subjects
89

89. References:
 Katzung – Basic & Clinical Pharmacology,
12th Edition
 Sharma – Priciples of Pharmacology,
2nd Edition
 K.D Tripathi
 www.fda.gov
 www.clinicaltrial.gov
 www.icmr.nic.in/guidelines/GCLP
 www.cdsco.nic.in/
 Fundamentals of clinical operations, Health care
sciences,SMU, MR0001
 Regulatory Affairs-I,Health care sciences,SMU, MR0002

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