CLINICAL TRIALS: TYPES AND DESIGN

Prepared by: Guided by:

Gadavala Sarah F. Dr. Ravi A. Manek
Assistant professor
En no: 202120825006
M.pharm, PhD
Mpharm 2nd sem pharmacology
SUB: CLINICAL RESEARCH AND PHARMACOVIGILANCE
B.K.MODY GOVT. PHARMACY COLLEGE,
RAJKOT
1
Flow of the Seminar
• Introduction
• History of clinical trials
• Types of clinical trial
• Phases of clinical trial
• Clinical trial Designs
• Observational
• Experimental
• Previously asked questions
• Reference 2
What is Clinical Trial ?

• It is a systematic study of new drug(s) in human subjects to generate

data for discovering and/or verifying the clinical, pharmacological,
and/or adverse effects with the objective of determining their safety
and/or efficacy of the new drugs.

• According to WHO clinical trial is may be defined as ‘any research

study that prospectively assigns human participants or groups of
humans to one or more health-related interventions to evaluate the
effects on health outcomes’.

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• Clinical trial are conducted only when:

• Satisfactory information has been gathered on the
quality of non clinical safety
• Health authority/ethics committee approval is
granted in the country where approval of the drug is
sought
• Clinical trial is the main stay for bringing out new
drugs to the market.
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History
• The first proper clinical trial was conducted by the physician
James Lind in 1747. He tested his theory that citric acids could
prevent and cure scurvy.

• Frederick Akbar Mahammad who worked at Guy’s Hospital

in London, made substantial contributions to the process of
clinical trials, where he separated chronic nephritis with
secondary hypertension.

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• The British Medical Research Council officially recognized the
importance of clinical trials from the 1930. The council established the
Therapeutic Trials Committee to advise and assist in the arrangement
of properly controlled clinical trials on a new products that have value
in disease treatment on experimental ground.
• In 1944 multicenter studies Conducting large trials at multiple
sites represented a significant change in how studies were
conducted. For the first time, trials were conducted at different
sites using the same protocol, with all the centers results
assessed together.
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• The first randomized curative trial was carried out at

the MRC Tuberculosis Research Unit by Sir Geoffrey
Marshall . The trial carried out between 1946-1947,
aimed to test the efficacy of the chemical streptomycin
for curing pulmonary tuberculosis. The trial was both
double blind and placebo controlled.

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Types Of Clinical Trials

• Treatment Trials: Test experimental treatments, new

combinations of drugs, or new approaches to surgery or
radiation therapy.

• Prevention Trials: Look for better ways to prevent disease

in people who have never had the disease or to prevent a
disease from returning. These approaches may include
medicines, vaccines, vitamins, minerals, or lifestyle changes.

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• Diagnostic Trials : Are conducted to find better tests or
procedures for diagnosing a particular disease or condition.
Diagnostic trials usually include people who have signs or
symptoms of the disease or condition being studies.

• Screening (Early Detection) Trials: test the best way to detect

certain diseases or health conditions.

• Quality Of Life Trials( or supportive care trials): explore

ways to improve comfort and the quality of life for individuals
with a chronic illness. 9
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Figure 1: Drug Development Process
Steps Involved In Designing A Pre-clinical Study

• Identifying a Drug Target:

• All drugs target specific points in biochemical pathways.

• Identifying the appropriate target step in the biochemical pathway is

critical and can determine the chances of success of the prospective
drug molecule.

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• Developing a Bioassay:
• A bioassay is a live system that is devised to measure the effects of a
drug.

• It varies from a cell or tissue culture system to organs or even a

whole living being.

• Screening the Drug in Bioassay:

• This is a screening test done with the bioassay to determine the
safety and effectiveness of the molecule.

• The drug must clear this step.

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• Establishing Effective and Toxic Doses:
• This step involves establishing the safe and toxic dose ranges.

• Future studies takes ideas from here about the dose ranges to be
tested in humans.

• Filling for an Approval as an IND (investigation new drug ):

• After all these steps are cleared the drug is fit for an application to
the FDA as an IND.
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Phase 0 Study/Micro dosing
• Study of new drug in micro dose to derive PK information in
human before undertaking phase 1 studies is called PHASE 0
study
• Micro dose: Less than 1/100 of the dose of a test substance
calculated to produce pharmacological effect with a max dose˂
100 micrograms
• Objective: To obtain preliminary efficacy, toxicity and
pharmacokinetic data
• Preclinical Data: Substance toxicity study in one species by
two routes of administration 14
Continue..

• These are very early studies of the PK & PD properties

of a potential drug in humans.
• 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.

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Advantages
• Less chances of adverse effects
• Short duration
• Less number of volunteers
• Reduced cost of development
• Reduced drug development time

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Disadvantages
• Study mainly based on PK parameters- not efficacy and
safety based
• Agents having different kinetic characteristics between
micro dose and full dose are not evaluated by phase 0
trials
• Of limited use for agents having Non linear PKs
• The laboratory parameters are very limited and
expensive researchers have to depend on labs
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Phases Of Clinical Trials

• Clinical trials involving new drugs are commonly classified into

four phases (I, II, III, & IV) each phase of the drug approval
process is treated as a separate clinical trial. If the drug
successfully passes through phase I, II and III, it will usually be
approved by the national regulatory authority for use in the
general population .
• Phase 4 are post-approval studies. Before pharmaceutical
companies start clinical trials on a drug, they conduct expensive
pre-clinical studies.
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Figure 2: Phases of Clinical trial 19
 PHASE I PHASE II PHASE III PHASE IV

OBJECTIVES: Determine the Evaluate effectiveness, Obtain additional Monitor ongoing safety
metabolic and determine the short- information about the in large populations and
pharmacological actions term side effects and effectiveness on clinical identify additional uses
and the maximally identify common risks outcomes and evaluate of the agent that might
tolerated dose for a specific population the overall risk-benefit be approved by the FDA
and disease ratio in a
demographically
diverse sample
FACTORS TO BE -Bioavailability -Bioavailability -Drug-disease -Epidemiological data
IDENTIFIED: -Bioequivalence -Drug-disease interactions -Efficacy and safety
-Dose proportionality interactions -Drug-drug interactions within large, diverse
-Metabolism -Drug-drug interactions -Dosage intervals populations
-Pharmacodynamics -Efficacy at various -Risk-benefit -Pharmacoeconomics
-Pharmacokinetics doses information
-Pharmacodynamics -Efficacy and safety for
-Pharmacokinetics subgroups
-Patient safety
DATA FOCUS: -Vital signs -Dose response and -Laboratory data -Efficacy
-Plasma and serum tolerance -Efficacy -Pharmacoeconomics
levels -Adverse events -Adverse events -Epidemiology
-Adverse events -Efficacy -Adverse events
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 PHASE I PHASE II PHASE III PHASE IV

DESIGN FEATURES: -Single, ascending dose -Placebo controlled -Randomized -Uncontrolled

tiers comparisons -Controlled -Observational
-Unblinded -Active controlled -2-3 treatment arms
-Uncontrolled comparisons -Broader eligibility
-Well-defined entry criteria
criteria

DURATION: Up to 1 month Several months Several years Ongoing (following

FDA approval)
POPULATION: Healthy volunteers or Individuals with target Individuals with target Individuals with target
individuals with the disease disease disease, as well as new
target disease (such as age groups, genders,
cancer or HIV) etc.

SAMPLE SIZE: 20 to 80 200 to 300 Hundreds to thousands Thousands

EXAMPLE: Study of a single dose Double-blind study
of Drug X in normal evaluating safety and
subjects efficacy of Drug X vs.
placebo in patients with
hypertension
Table 1: Phases of Clinical Trial
Study of Drug X vs. Study of economic
standard treatment in benefit of newly-
hypertension study approved Drug X vs.
standard treatment for
hypertension
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Designs of clinical trials

Observationa
Experimental
l

Analytical RCT

Descriptive Non RCT

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Further Classification Of Observational
Study Design

Analytical Descriptive

Case
Cohort
report

Case Case
control series

Cross
Surveys
sectional
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Observational Study Design
• In observational study the subjects or recruited population are
just observed, as name indicates no interventions are taken
place.
• Based on the time, observational study designs are further
categorized into analytical study and descriptive study. And
main goal of the various study designs include:

 Descriptive study is to generate hypothesis,

 Analytical study is to test hypothesis and
 Experimental study is to prove hypothesis. 24
Cohort Study Design
• Cohort study also named as: Follow up study, Forward looking study, Incidence study,
Longitudinal study
• A cohort study is a study, starts with exposure (risk factor) and follow for the outcome (disease)
• study consists two group’s first group is exposed to some risk factor and second group free from
exposure
• Then follow the each group to find out the disease status
• Compare the disease risk between exposed group and unexposed group
Disease (lung
cancer)
Exposed
(smoking)
No disease
Population
(sample) Disease (lung
cancer)
unexposed
No disease25
The studies may be :
1. Prospective :
• A group of people is chosen who do not have the outcome of interest (for
example, myocardial infarction).
• The investigator then measures a variety of Variables that might be relevant to the
Development of the condition.
• Studies carried out from present time to future
• Can be tailored to collect specific exposure rate
• But long wait for events to occur
• Expensive
• Prone to high dropout rates
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2. Retrospective

• These use data already collected for other purposes. The

methodology is the same but the study is performed.
• Outcome is already developed.
• Look at medical events from past to present
• Information is available immediately
• Difficulty in tracing subjects and doubt on quality of recorded
information
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Case Control Study Design
• An observational study that compares patients who have a disease or outcome of
interest (cases) with patients who do not have the disease or outcome (controls),
and looks back retrospectively to compare how frequently the exposure to a risk
factor is present in each group.

Study base

Control
Cases (50)
(50)

Exposed Unexposed Exposed Unexposed

(40) (10) (15) (35)

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Continue…

• Odds ratio= (no of exposed cases)/(no of unexposed cases)

(no of exposed control)/(no of unexposed controls)

Odds Ratio : 40/10x35/15 = 4 x 2.33= 9.33

odds of exposure for cases is 9.33 times that of controls

Exposure is associated with 9x greater chance of disease.

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Advantages
• Efficient- saves time and energy
• Used for rare diseases, small sample sizes
• Can generate hypothesis for future study

Disadvantages
• Susceptible to bias-recall, reporting
• Prone to methodological errors
• Selection of an appropriate comparison group may be difficult

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Cross sectional Study Design
• Is a type of observational study that are primarily used to
determine prevalence.
• Prevalence equals the number of cases in a population at a
given point in time.
• All the measurements on each person are made at one point in
time.

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Calculating prevalence
• The prevalence of a health outcome is simply the proportion of individuals with
the health outcome in a population.
• Prevalence= cases/ total population
• Example:
Present CHD Absent CHD Total
Not active 50a 200b 250
Active 50c 700d 750
Total 100 900 1000
Table 2: Cross sectional study

• P1= a/a+b= 50/250 = 20.0% prevalence of CHD among people who are not active.
• P0= c/c+d = 50/750 = 6.7% prevalence of CHD among people who are active.
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Experimental Study Design
• Experimental study (clinical trial) A type of clinical study in which
participants are assigned to groups that receive one or more
intervention/treatment (or no intervention) so that researchers can
evaluate the effects of the interventions on health-related outcomes.
• Interventions may be medical products, such as drugs or devices,
procedures or changes to participants behavior.
Experimental
study

Quaci True
experimental experimental
study (Non RCT) study(RCT) 33
Non randomized controlled Design
• Also called quaci interventional study design
• In non randomly assigned control group studies, at least two
separate groups are evaluated
• One of which receives the intervention of interest and another
that serves as a control or comparison group.
• That means it is used to estimate the causal impact of an
intervention on its target population without random
assignment.
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Reasons to do non randomized controlled study
• When the act of random allocation may reduce the effectiveness of the
intervention (occurs when the effectiveness of the intervention depends on the
participant’s active participation which is influenced by their beliefs and
preferences)
• When it would be unethical to do random allocation
• When it is impractical to do random allocation (e.g. Cost or convenience factors)
• When there are legal or political obstacles to random allocation
• When researchers can’t manipulate the independent variables
• When researchers can’t randomly assign participants to groups.
• Quasi independent variable is a naturally occurring variable and can’t be
manipulated or eliminated.
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Types Of Non Randomized controlled
study Design

One group pre test post test design

Non equivalent control group design

Interrupted time series design

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 One group pre test post test design

Time 1 Intervention Time 2

01 X 02

Example: Sample of violent adolescent women

Treatment: anger management class
Measures: aggressive behavior 1 year pre/post treatment

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Non equivalent control group design

Target
population
Intervention
Pre test Post test
X
selection
Activity as
Pre test Post test
usual

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Interrupted time series design
• Time series analysis is simply a set of measurements of a
variable taken at various points in Time.
• Essentially, the investigator measures the outcome of interest
several times before initiating the experiment to establish a
baseline value and trend in the data. After the intervention,
the investigator will again measure the outcome several times
to establish the impact of the intervention.
• Example: Mood of students during semester

T1 T2 T3 T4 T5 T6 T7 T8 T9
A B C D X E F G H
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Randomized Control Study Design (RCT)
• An epidemiological experiment in which subjects in a population are
randomly allocated into groups, usually called study and control
groups, to receive or not receive an experimental preventive or
therapeutic
• Patients are randomly assigned to the study all groups that help in
avoiding bias in patient outcome
Interventio
n group No
Study outcome
population
Outcome
Control
group No
outcome 40
Advantages
• Comparative
• One treatment is directly compared to another to establish superiority.
• Minimizes bias
• Randomization minimizes allocation bias and selection bias
• Blinding minimizes performance bias
• Randomization makes groups comparable according both known and
unknown factors
• Statistical reliability
• Statistical test of significance is readily interpretable when the study is
randomized
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Disadvantages

• Might demand vast samples size, which require more resources from
the investigators
• Sometimes allocation of participants may be predictable and result in
selection bias when the study groups are unmasked
• Trials are of longer duration and more expensive
• Results may not always mimic real life treatment situation (e.g.
Inclusion / exclusion criteria; highly controlled setting)

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Types of RCT

• Randomized Controlled Clinical Trial includes Diagnostic,

Therapeutic, Prophylactic
• e.g. Evaluation of nitrates in reducing cardiovascular mortality

• Randomized Controlled Field Trial: It is similar to an

Randomized Controlled Clinical Trial except that the
intervention is preventive and not therapeutic.
• e.g. In this, the efficacy of a preventive intervention such as a new
vaccine is tested in one study group and the other group receives a
placebo or standard 43
Continue..

• Preventive Trial: Trial of primary preventive measures

• e.g. Vaccines

• Risk Factor Trial: Investigator intervenes to interrupt the

usual sequence in the development of disease for those
individuals who have risk factor for developing the disease
• e.g. Primary prevention of CHD using simvastatin to lower
serum cholesterol

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Further classification
• According To Blinding

1. Open RCT: In open RCT, everybody involved in the trial knows which
intervention is given to each participant

2. Single blind: Patient or evaluator is blinded as to treatment, but not both

3. Double blind: Neither patient nor outcome evaluator knows to which treatment
patient was assigned

4. Triple blind: Patient, physician, and data analyst are blinded as to treatment
identity 45
According To Participants Exposure

Parallel
Crossover
Cluster
Factorial
Adaptive
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Parallel
• A parallel study is a type of clinical study where treatment and
controls are allocated to different individuals.
• In this two groups of treatments, a and b, are given so that one
group receives only a while another group receives only b.

Evaluation
Treatment
of
Study A outcomes
population Treatment
B
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Cross Over Design
• In these types of studies each patient serves as his own control.
Each patient gets both treatments.
• Each patient receive first treatment then washout time is
provided then other treatment is provided to the same.
Treatment
Treatment Washout B
Study A period Treatment
population Treatment A
B
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Cluster Design
• Type of randomized controlled trial wherein groups of participants
(as opposed to individual participants) are randomized and made
into clusters.
• Cluster means group and this study itself consists subjects as
randomization
• The study goes on group wise, not on the basis of individuals
• Examples for group includes – Schools in a city, Villages,
Religion, Ethnicity and Occupation wise in an area
• This is the simple to randomize the participants by groups than
individual
• Even the results are done by group not by individuals 49
Factorial Design
• Studies involving two or more factors while randomizing are
called factorial

• Factorial design permits researchers to investigate the joint

effect of two or more factors on a dependent variable.

• Used when it is desired to study the influence of a number of

factors on the treatments compared as well as their interaction
with different treatments factors on a dependent variables
designs 50
Adaptive Trial Design

Figure 3: Adaptive trial design 51

According To Number Of Participants
1.N-of-one trials
• An N of 1 trial is a clinical trial in which a single patient is the entire trial, a single
case study, In which one participant receives the experimental and the control
interventions.
2. Mega trials
• A massive clinical trial assessing the value of the therapeutic interventions by
enrolling 10,000 or more subjects.
3. Sequential trials
• It is a statistical analysis where the number of participants is not specified by the
investigators beforehand.
• Instead, the investigators continue recruiting participants until a clear benefit of
one of the interventions is observed.
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Bias

•Bias or errors in the study causes the results inaccurate. The different biases
include,

1.
Confounding Bias
• Confounder is an additional risk factor or variable related with
exposure/disease that affects the outcome (other than the risk factor).

2. Selection Bias
• Selection bias is a problem in observational studies why because in which
groups are not randomized, Groups assigned as their wish. If groups are not
balanced based on the characteristics, we get irregular and unbalanced
groups, ultimately it effects on results. 53
Continue..
3.Information Bias
• The inaccurate information collected from subjects, results in giving the wrong
outcome. This inaccurate information may come from the either subjects or
personnel.

4. Protopathic Bias
• The electing of a diseased person but not recognized during commencing the
study, disease may appear after the drug intake cause to misleading of the
study.

5. Measurement Bias
• If many groups are involved in the study, the personnel measuring and
instruments used are the two major problems to arise this bias. 54
Randomization

• it is well-established methodology adopted in research to prevent bias due to

subject selection, which may impact the result of the intervention/experiment
being studied.

• one of the fundamental principles of an experimental study designs

• ensures scientific validity

• provides a way to avoid predicting which subjects are assigned to a certain group
and therefore, prevent bias on the final results due to subject selection.
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Continue..
• also ensures comparability between groups as most baseline characteristics are
similar prior to randomization and therefore helps to interpret the results regarding
the intervention/experiment group without bias.

• There are various ways to randomize and it can be as simple as a ‘flip of a coin’ to
use computer software and statistical methods

• To better describe randomization, there are three types of randomization: simple

randomization, block randomization and stratified randomization

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Placebo

• Placebo is defined in the Merriam-Webster dictionary as ‘an inert or innocuous

substance used especially in controlled experiments testing the efficacy of
another substance (such as drug)’.
• In clinical drug trials, a placebo is typically a drug that resembles the drug to be
tested in certain characteristics such as color, size, shape and taste, but without
the active substance. This helps to measure effects of just taking the drug, such as
pain relief, compared to the drug with the active substance.
• If the effect is positive, for example, improvement in mood/pain, then it is called
placebo effect.
• If the effect is negative, for example, worsening of mood/pain, then it is called
nocebo effect.
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Previously Asked Questions
1. Enlist different types of experimental studies. Write the advantage of RCT over Non-RCT
( GTU Summer 2019 )
2. Explain in brief case control and cross sectional study. ( GTU Summer 2019 )
3. Write a note on prospective and retrospective cohort study with giving suitable example.
( GTU Summer 2019 )
4. Define passive surveillance study and describe cohort study by giving suitable example.
( GTU Summer 2018 )
5. Write the advantages and disadvantages of RCT and Non-RCT. ( GTU Summer 2018 )
6. Explain the flow of drug development process. Discuss the phase-Ill of the same in detail .
( GTU Summer 2018 )
7. Differentiate between active surveillance and passive surveillance studies. Give the detail on
case report study using suitable example. ( GTU Summer 2019 )
8. Explain the terms randomized control trial and non-randomized control studies with
examples. ( GTU Summer 2019 ) 58
Reference
• Pradeep Battula, Divya Gopineni, Durga Prasad T S, Chenchugari Sridhar, Clinical Research Study Design: A Review, Inventi Rapid:
Clinical Research, Vol. 2015, Issue:3
• Ambika G. Chidambaram Maureen Josephson, Clinical research study designs: The essentials, Pediatr Invest 2019 Dec; 3(4): 245-252
• UK Clinical research Collaboration (UKCRC), Booklet on Understanding Clinical trials, 1st Edition, www.ukcrc.org
• Schedule Y(ammended version)- CDSCO, http://rgcb.res.in/documents/schedule-Y
• History of clinical research, http://www.imaecresearch.com/clinical-research-timeline-history
• Lucy Mastrandrea and Takara Stanley Study Designs and Basic Statistics & PES Fellow Education Committee, Pediatric
Endocrinology 10/19/12
• http://www.google.com
• http://www.slideshare.net
• Wikipedia
• “Publishing and Presenting clinical Research”,third edition by S. Warren
• “Practical Guide to Clinical Data Management”, third edition by P.S.
• “Fundamentals of Clinical Trials”, 4th edition by F.M. Lawrence
• Mann, C.J., 2003. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emergency
medicine journal, 20(1), pp.54-60.
• Grimes, D.A. and Schulz, K.F., 2002. Bias and causal associations in observational research. The Lancet, 359(9302), pp.248-252.
59
• www.who.int/topics/clinical_trials/en
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