An Introduction to

Clinical Research and Drug

Development
• What is Clinical Research?
• How Clinical Research is
performed?
• How to develop a Clinical
Research study?
• How to identify and test new drug?
Clinical Trials Overview

A clinical trial is a medical

research study conducted to
find answers to health
questions
Clinical Trials Overview
WHY ???
Clinical trials are often conducted to
• Evaluate new medications
• A combination of medications, OR
•New ways to use current treatments
Clinical Trials Overview
WHY ???
Clinical trials are also conducted to
• Evaluate new tests
• Equipment and procedures for
diagnosing and detecting health
conditions and
• Find vaccines to prevent illnesses
Clinical Trials Overview
On whom should I do ???

HUMANS
Clinical Trials Overview
If so, can I do the study directly
on Humans???
Before an experimental treatment can be
tested in a clinical trial,
• It must have shown benefit in
laboratory testing
• Animal research studies, OR
• Research in a small group of humans
Clinical Trials Overview
Why are Clinical Trials so
important???
• Clinical trials translate results of basic
scientific research into better ways to
• Prevent
• Diagnose OR
• Treat disease
Clinical Trials Overview
Leading Therapeutic Areas for
Clinical Trial Services, 2015
Clinical Trials Overview
R&D Spending for
Clinical Trial Services

SOURCE
Left chart, EvaluatePharma. Right chart: Genetic Engineering & Biotechnology News,
March 2014.
 The Language
of Clinical Trials
 People and Entities

• Sponsor
• Principal Investigator (PI)
• Sub-investigator
• Sponsor-Investigator
• CRO (Contract Research Organization)
• CRA (Contract Research Associate)
• Study Coordinator, CRC (Clinical Research
Coordinator)
 Sponsor
• An individual, company, institution, or
organization that takes responsibility for the
initiation and management of a clinical trial,
although may or may not be the main funding
organization.

• A corporation or agency whose employees

conduct the investigation is considered a sponsor
and the employees are considered investigators.
 Principal Investigator (PI)
An individual who actually conducts a clinical
investigation i.e., under whose immediate
direction the test article (drug) is
• administered or
• dispensed to, or
• used involving a subject, or
• in the event of an investigation conducted by a
team of individuals, is the responsible leader of
that team.
 Sub-investigator
Any member of the clinical trial team
designated and supervised by the
investigator at a trial site
• to perform critical trial-related procedures
and/or
• to make important trial-related decisions
(e.g., associates, residents, research
fellows).
Delegation of Responsibility Log
• List of individuals to whom the PI has delegated
authority to conduct assessments, procedures,
data capture, informed consent process, or any
aspect of the clinical trial
 Sponsor-Investigator

• An individual who both initiates and conducts,

alone or with others, a clinical trial and under
whose immediate direction the investigational
product is administered to, dispensed to, or used
by a subject.

• NOTE: The term does not include any person

other than an individual (i.e., it does not
include a corporation or an agency).
 CRO
• Contract Research Organization

• A person or an organization (commercial,

academic, or other) contracted by the sponsor
to perform one or more of a sponsor's trial-
related duties and functions.

• 21CFR312.52: Transfer of Obligations to a CRO

– CRO shall comply with the same regulations
– CRO is subject to the same regulatory actions
 CRA, Monitor
• Person employed by a sponsor or CRO acting on a
sponsor's behalf, who monitors the progress of
investigator sites participating in a clinical study.
– Responsible for determining that a trial is being conducted
in accordance with the protocol and GCP guidance.
– At some sites (primarily in academic settings), clinical
research coordinators are called CRAs.

• A monitor's duties may include but are not limited to

helping to plan and initiate a trial, assessing the
conduct of trials, and assisting in data analysis,
interpretation, and extrapolation.
 Clinical Research Coordinator
• Person who handles most of the administrative
responsibilities of a clinical trial on behalf of a
site investigator, acts as liaison between
investigative site and sponsor, and reviews all
data and records before a monitor's visit.

• Synonyms: trial coordinator, study coordinator,

research coordinator, clinical coordinator,
research nurse, protocol nurse.
 The Study

• Protocol
• Protocol deviation
• Protocol violation
• Protocol amendment
 Protocol

• A document that describes the objective(s),

design, methodology, statistical considerations,
and organization of a trial.
• Usually also gives the background and rationale
for the trial, but these could be provided in other
protocol referenced documents.
• Detailed imaging parameters may not be
included in a therapeutic protocol
 Protocol Deviation
• A variation from processes or procedures
defined in a protocol.

• Usually do not preclude the overall evaluability

of subject data for either efficacy or safety.

• Can be acknowledged and accepted in advance

by the sponsor “Protocol exception”
 Protocol Violation
• A significant departure from processes or
procedures that were required by the protocol.

• Often result in data that are not deemed

evaluable for a per-protocol analysis

• May require that the subject(s) who violate the

protocol be discontinued from the study.
 Protocol Amendment
• A written description of a change(s) to or formal
clarification of a protocol.

• Must be approved by IRB prior to

implementation
 Data Capture and Recording

• Case Report Form

• Source Document
• Electronic Data Capture (EDC)
• Clinical Study Report, Clinical Trial Report
• Database lock
 Case Report Form
• A printed, optical, or electronic document
designed to record all of the protocol-required
information to be reported to the sponsor for
each trial subject.

• A record of clinical study observations and other

information that a study protocol designates
must be completed for each subject.
 Source Document
• Original documents
• Records e.g.,
• hospital records
• laboratory notes
• subjects' diaries
• pharmacy dispensing records
• recorded data from automated instruments
• x-rays and
• records kept at the pharmacy, at the laboratories, and at
medicotechnical departments involved in the clinical trial
 EDC
• The process of collecting clinical trial data into
a permanent electronic form.

• NOTE: Permanent in the context of these

definitions implies that any changes made to the
electronic data are recorded with an audit trail.
 Clinical Study Report
• A written description of a study of any
treatment or diagnostic agent conducted in
human subjects

• Includes clinical and statistical description,

presentations, and analysis
 Database Lock

• Action taken to prevent further

changes to a clinical trial database.

• NOTE: Locking of a database is done after

review, query resolution, and a determination
has been made that the database is ready for
analysis
Understanding Clinical Trials
Understanding the clinical trial in regards
of;
•Design
•Analysis
•Reporting
In a very simple manner
Types of studies

•Experimental study
•Observational study
•Reviews
Types of studies

Experimental study
•Controlled
•Uncontrolled
Observational study
Types of studies

Experimental study
•Controlled
• Parallel
• Sequential
•Uncontrolled
Observational study
Types of studies
Experimental study
•Controlled
• Parallel
• Randomized
• Non randomized
• Sequential
•Uncontrolled
Observational study
Types of studies
Experimental study
• Controlled
• Parallel
• Sequential
• Self control
• Crossover
• Uncontrolled
Observational study
Types of studies
Experimental study
• Controlled
• Parallel
• Randomized
• Non randomized
• Sequential
• Self control
• Crossover
• Uncontrolled
Observational study
Clinical Trials in India :
The National Perspective
India: A preferred destination for
clinical trials
Some of the advantages that India
offers as clinical trials destination are
as follows:
•High degree of compliance to international
guidelines such as the ICH GCP and the
regulations lay down by the US Food and Drug
Administration.

•Availability of well qualified, English speaking

research professionals including physicians.
Some of the advantages that India offers
as clinical trials destination are as follows:

• Ongoing support and cooperation

from the government.
• Lower cost compared to the west.
• Increasing prevalence of illnesses
common to both developed and
developing countries.
• Availability of good infrastructure.
• Changes in Patent Laws since
January 2005.
As per a recent report from FICCI (Federation of
Indian Chambers of Commerce and Industry)
•scientific feasibility
•medical infrastructure
•clinical trial experience
•regulations
•commercialization potential and
•cost competitiveness
are some of the growth drivers responsible
for the metamorphosis of Indian clinical
research in the recent past.
 SWOT Analysis of
Indian Clinical Trial Sector

Strengths
•Large population of over 1.34 billion, about
17.84% of the world’s population.
•Huge pharmaceutical and biotech industry
base with availability of skilled persons.
•8% of global pharmaceutical production,
being 4th in the world.
Agencies Involved for Clinical
Research Regulation In India
Various agencies of India with their
prominent role in overseeing clinical trial
along with Ethics committee
 Agencies
1.Drug Controller General of India (DCGI)
2.Central Drugs Standard Control Organization
(CDSCO)
3.Department of Biotechnology (DBT)
4.Ministry of Environment and Forest (MoEF)
5.Indian Council of Medical Research (ICMR)
6.Central Bureau of Narcotics (CBN)
7.Ministry of Health and Family Welfare (MoHFW)
8.National Pharmacovigilance & Advisory
Committee (NPAC)
CLINICAL RESEARCH
METHODS
Study Design
 Study Design
• Bias and variability
• Randomization: why and how?
• Blinding: why and how?
• General study designs
 Bias and Variability
• The clinical trial is considered to be the
“gold standard” in clinical research

• Clinical trials provide the ability to reduce

bias and variability that can obscure the
true effects of treatment

• Bias  affects accuracy

• Variability  affects precision
• Bias: any influence which acts to make the
observed results non-representative of the
true effect of therapy
• Examples:
– healthier patients given treatment A, sicker
patients given treatment B
– treatment A is “new and exciting” so both
the physician and the patient expect better
results on A
• Many potential sources of bias
• Variability: high variability makes it more
difficult to discern treatment differences
• Some sources of variability
– Measurement
instrument
observer
– Biologic
within individuals
between individuals
• Can not always control for all sources
(and may not want to)
 Fundamental principle
in comparing treatment groups
• Groups must be alike in all important
aspects and only differ in the treatment
each group receives

• In practical terms, “comparable treatment

groups” means “alike on the average”
 Why is this important?
• If there is a group imbalance for an
important factor then
– an observed treatment difference may
be due to the imbalance rather than
the effect of treatment
How can we ensure comparability
of treatment groups?
• We can not ensure comparability but
randomization helps to balance all
factors between treatment groups
• If randomization “works” then groups will
be similar in all aspects except for the
treatment received
 Randomization
• Allocation of treatments to participants is
carried out using a chance mechanism
so that neither the patient nor the
physician know in advance which
therapy will be assigned

• Simplest Case: each patient has the same

chance of receiving any of the treatments
under study
 Simple Randomization
 Think of tossing a coin each time a subject is
eligible to be randomized
 HEADS: Treatment A
 TAILS: Treatment B
 Approximately ½ will be assigned to
treatments A and B
 Randomization usually done using a
randomization schedule or a computerized
random number generator
 Problem with Simple
Randomization
• May result in substantial imbalance in
the number of subjects assigned to
each group

• Solution: Use blocking and/or

stratified randomization
 Blocking Example
• If we have two treatment groups (A
and B) equal allocation, and a block size of
4, random assignments would be chosen from
the blocks
1) AABB 4) BABA
2) ABAB 5) BAAB
3) ABBA 6) BBAA
• Blocking ensures balance after every 4th
assignment
 Stratification Example
• To ensure balance on an important baseline
factor, create strata and set up separate
randomization schedules within each stratum
• Example: if we want to prevent an imbalance on
age in an osteoporosis study, first create the
strata “< 75 years” and “ 75 years”
then randomize within each stratum
separately
• Blocking should be also be used within each
stratum
 Blinding
• Masking the identity of the assigned interventions
• Main goal: avoid potential bias caused by
conscious or subconscious factors
• Single blind: patient is blinded
• Double blind: patient and assessing
investigator are blinded
• Triple blind: committee monitoring
response variables (e.g.
statistician) is also blinded
 How to Blind ?
• To “blind” patients, can use a placebo

Examples
– pill of same size, color, shape as
treatment
– sham operation - is a faked surgical
intervention (anesthesia and incision)
for angina relief
 Why Should Patients be
Blinded?
• Patients who know they are receiving a new or
experimental intervention may report more (or less)
side effects
• Patients not on new or experimental treatment
may be more (or less) likely to drop out of the study
• Patient may have preconceived notions about the
benefits of therapy
• Patients try to get well/please physicians
Why Should Investigators
be Blinded?
 Treating physicians and outcome
assessing investigators are often
the same people
  Possibility of unconscious bias in
assessing outcome is difficult to rule out
 Can Blinding
Always be Done?
• In some studies it may be impossible
(or unethical) to blind
– a treatment may have characteristic
side effects
– it may be difficult to blind the
physician in a surgery or device study
• Sources of bias in an un-blinded study
must be considered
 Study Design
• Bias and variability
• Randomization: why and how?
• Blinding: why and how?
• General study designs
 General Study Designs
• Many clinical trial study designs fall into
the categories of parallel group, dose-
ranging, cross-over and factorial
designs
 General Study Designs
• Parallel group designs
B A
R
A B
N
D C
control
 General Study Designs
• Dose-Ranging Studies
high dose
B
R
medium dose
A
N
low dose
D
control
 General Study Designs
• Cross-Over Designs
WASH- OUT

B
A B
R
A
N
D
B A
 Cross-Over Designs
• Subjects are randomized to sequences of
treatments (A then B or B then A)
• Often a “wash-out” period (time between
treatment periods) is used to avoid a “carry
over” effect (the effect of treatment in the
first period affecting outcomes in the second
period)
 Cross-Over Designs
• Advantage: treatment comparison is only
subject to within-subject variability not
between-subject variability
  reduced sample sizes
• Disadvantages:
– strict assumption about carry-over effects
– inappropriate for certain acute diseases
(where a condition may be cured during the
first period)
– drop outs before second period
 General Study Designs
• Factorial Designs
A+B
B
R
A A + control
N
D B + control

control + control
 Factorial Designs
• Advantages:
– If no interaction, can perform two
experiments with less patients than
performing two separate experiments
• Disadvantages:
– Added complexity
– potential for adverse effects due to
“poly-pharmacy”
COHORT STUDY
 Design of Cohort Studies
What is a cohort ?
• Cohort: group of individual with a common
characteristic who are followed over a period of
time
e.g. A smoker’s cohort means all are smokers in
that group

• Selection of cohorts based on exposed and

unexposed individuals to follow in specified time
or until development of outcome (disease/death)
 EXPOSED NOT EXPOSED

DEVELOP DO NOT DEVELOP DO NOT

DEVELOP DISEASE DEVELOP
DISEASE DISEASE DISEASE

Design of a COHORT Study

 Cohort Study (Prospective)
Disease occurs

Exposed

No disease

Disease occurs
Unexposed

No disease

2016 Present Future

 Cohort Study (Retrospective)
Disease occurs

Exposed

No disease

Disease occurs
Unexposed

No disease

Examine exposure in medical

records /census/available data Present 2016
1995 Past
 Frame work of Cohort
studies
Disease Status
Total Yes No

Study
Yes a+b a b
Exposure cohort

Status No Comparison
c+d c d cohort

N a+c b+d
 Relative Risk (RR)
Diseased Not diseased
Exposed a b
Unexposed c d

RR = Incidence in exposed
Incidence in unexposed
 Interpretation of
Relative Risk (RR)
RR =1: No association between
exposure and disease incidence rates are
identical between groups

RR >1: Positive association

(increased risk)
risk exposed group has higher
incidence than unexposed group

RR <1: Negative association

(protective effect)
effect unexposed group has
higher incidence than exposed group
 Example: Relative Risk
Calculation

Incidence in smokers = 84/3000 = 28.0/1000/yr

Incidence in non-smokers = 87/5000 = 17.4/1000/yr
Relative risk = 28.0/17.4 = 1.61
Double Dummy Method

Subjects receive similar

regimens (drugs) with
respect to appearance,
when different drugs look
different
 GUIDELINE FOR
GOOD CLINICAL PRACTICE
Good Clinical Practice (GCP) is an
international ethical and scientific
quality standard for
• designing
• conducting
• recording and reporting trials
that involve the participation of
human subjects.
Compliance with this standard
provides
public assurance that the
• rights
• safety and well-being of trial
subjects are protected.
WHO Principles
of GCP
Principle 1:
Research involving humans should be
scientifically sound and conducted
in accordance with basic ethical
principles
Three basic ethical principles of equal
importance, namely
• respect for persons
• beneficence, and
• justice
Principle 2:
Research involving humans
should be
scientifically justified
and described in a clear,
detailed protocol.
Principle 3:
Before research involving
humans is initiated,
• foreseeable risks and
• discomforts and any
• anticipated benefit(s) for
the individual trial subject and
society should be identified.
Principle 4:
Freely given informed
consent should be obtained
from every subject prior to
research participation.
Principle 5:
Research involving humans
should be continued only
if the benefit-risk profile
remains favourable.
Principle 6:
Qualified and duly licensed
medical personnel (i.e., physician)
should be
• responsible for the medical
care of trial subjects, and for
• any medical decision(s) made.
Principle 7:
Each individual involved in
conducting a trial should be
• qualified by education,
• training, and
• experience to perform his or
her respective task(s) and
currently licensed to do so,
where required.
Principle 8:
All clinical trial information
should be
recorded
handled, and stored in a
way that allows
its accurate reporting
interpretation, and
verification.
 CLINICAL TRIAL
PROTOCOL DESIGN
AND DEVELOPMENT
The contents of a trial
protocol should
generally include the
following topics
General Information
•Protocol title, protocol identifying
number, and date. Any amendment(s)
should also bear the amendment
number(s) and date(s).
General Information
•Name and address of the sponsor and
monitor (if other than the sponsor).
General Information

•Name and title of the person(s)

authorized to sign the protocol
and the protocol amendment(s)
for the sponsor.
General Information
•Name and title of the investigator(s)
who is (are) responsible for
conducting the trial, and the address
and telephone number(s) of the trial
site(s).
General Information
•Name, title, address, and telephone
number(s) of the qualified physician,
who is responsible for all trial-site
related medical decisions (if other
than investigator).
Background Information
•Name and description of the
investigational product(s).
•A summary of findings from
nonclinical studies.
•Summary of the known and potential
risks and benefits, if any, to human
subjects.
Background Information

•Description for the route of

administration, treatment
period(s).
•Description of the population to
be studied.