Clinical Study: Design
and Methods
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
King Faisal Specialist Hospital & Research
Centre
1
Definitions of Research
“Systematic investigation towards increasing the sum of
knowledge”
(Chambers 20th Century Dictionary)
“an endeavour to discover new or collate old facts etc.
by the scientific study of a subject or by a course of
critical investigation.”
(The Concise Oxford Dictionary)
2
Where to Start?

A good clinical study starts with


a good question based on good hypothesis that is based on
good and comprehensive review of the available evidence
from pre-clinical and clinical data
Type of design depends on the question to be
answered
3
Formulating a Research Question


Focused and specific

What is the prevalence of Hepatitis B surface Antigen in Saudi Arabia?

What are the risk factors for hepatitis B infection? Prospective cohort or case-

Is interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial

Is vancomycin better than ceftazidime against gram negative organisms?
Not a replication of already established evidence


control
Supported by available data


Cross-sectional study
Is smoking associated with lung cancer?
Ethical
Answerable

Methods, resources ….etc
4
Objectives

Specific aims


Clear and detailed
End point(s)

Primary


The main answer to the research question
Secondary

Answer other related questions
5
Study Design

Your question



Your resources



Describe
Analyze
Retrospective
Prospective
Community

Acceptance of research


Observational
Interventional
6
Clinical Study Types

Observational Studies






Cohort (Incidence, Longitudinal)
Case-Control
Cross-Sectional (Prevalence)
Case Series
Case Report
Experimental Studies


Uncontrolled Trials
Controlled Trials
7
Levels of Evidence
Hierarchy of Strength of Evidence for Treatment Decisions
Level I:
Level I (A):
Level I (B):
Level II (A):
Level II (B):
Level III:
Level IV:
N of 1 randomized trial (double-blinded, cross-over)
Systematic reviews of randomized trials
Single randomized trial
Systematic review of observational studies addressing
patient-important outcome
Single observational study addressing important outcome
Physiologic studies
Unsystematic clinical observations (case-reports, anecdotal)
JAMA 2000; 284(10):1290-96
8
Observational study  Clinical trial
describe as
occurring in nature
observational
study
exposed
outcome
allocate
randomly
non exposed
Clinical
Trial
Ethics!
9
Important issues in Study Design

Validity: Truth

External Validity:


Internal Validity:


Can the study be generalized to the population
Results will not be due to chance, bias or confounding factors
Symmetry Principle: Groups are similar
10
Important issues in Study Design


Confounding: distortion of the effect of one risk factor by the presence
of another
Bias: Any effect from design, execution, & interpretation that shifts or
influences results



Confounding bias: failure to account for the effect of one or more
variables that are not distributed equally
Measurement bias: measurement methods differ between groups
Sampling (selection) bias: design and execution errors in
sampling
11
Introduction
Why this study is needed ?
What is the purpose of this study?
 Was purpose known before the study?
 What has been done before and how does this
study differ?


inadequacies of earlier work or next step in an
overall research project
Does the location of the study have relevance?
12
Why doing a study?

Alternative:
 census: test every individual in the population
 use available data, e.g. hospitals
But:
- data availability
- data quality
- cost
- questions require specific type of data and
circumstances
13
Types of observational studies

CROSS - SECTIONAL STUDY

COHORT STUDY

CASE CONTROL STUDY

CASE SERIES/CASE REPORTS
14
Characteristics of observational studies

No control over study units




need to clearly describe study individuals
Can study risk factors that have serious consequences
Study individuals in their natural environment (>>
extrapolation)
Possibility of confounding
15
Aims of observational studies

Evaluate the effect of a suspected
risk factor (exposure) on an outcome
(e.g. disease)
 define ‘exposure’ and ‘disease’

Describe the impact of the risk factor
on the frequency of disease in a
population
16
Cross - Sectional Study
17
Cross - Sectional Study (1)

Exposure and disease measured once, i.e. at the same
point in time
n
exposed ?
diseased ?
past
present
future
18
Cross - Sectional Study (2)

Random sample from population




i.e. results reflect reference population
Estimates the frequencies of both exposure and
outcome in the population
Measuring both exposure and outcome at one point
in time
Typically a survey
19
Cross - Sectional Study (3)






Can study several exposure factors and outcomes
simultaneously
Determines disease prevalence
Helpful in public health administration & planning
Quick
Low cost (e.g. mail survey)
Limitation:


Does not determine causal relationship
Not appropriate if either exposure or outcome is rare
20
Pediatricians per
1000 Children
Cross-Sectional: Pediatrician-to-Child Ratio
40
35
30
25
20
15
10
5
0
1981
1986
1991
1996
Rural
Urban
Greg et al. (2001) Pediatrics.107(2):e18
21
Cross-Sectional: Risk Factors for Smoking
Variable
No. friends who smoke:
- all vs. none of them
- most vs. none of them
- about half vs. none of them
- a few vs. none of them
Any siblings who smoke: Y vs. N
OR
95% CI
36.5
18.4
7.5
2.1
2.8
9.3 – 142.8
5.5 – 61.8
2.2 – 26.0
0.6 – 7.9
1.8 – 4.3
Mother smokes:
Yes vs. No
Have no mother vs No
1.9
3.5
1.3 – 2.9
0.8 – 15.0
22
Cohort Studies
23
Cohort studies

Follow-up studies; subjects selected on presence or
absence of exposure & absence of disease at one
point in time. Disease is then assessed for all subjects
at another point in time.

Typically prospective but can be retrospective,
depending on temporal relationship between study
initiation & occurrence of disease.
24
Cohort Study (1)

Individuals selected by exposure status and future
occurrence of disease measured
n
n
Exposed yes
no
past
disease
?
yes
Exposed
disease ?
no
present
disease ?
disease ?
future
25
Cohort studies (2)



More clearly established temporal sequence
between exposure & disease
Allows direct measurement of incidence
Examines multiple effects of a single exposure
(nurses’ health study, OC and breast, ovarioan
cancers)
26
Cohort studies (3)

Limitations:
 time consuming and expensive
 loss to follow-up & unavailability of data
 potential confounding factors
 inefficient for rare diseases
27
Prospective Cohort Study
with outcome
Exposed
without
outcome
Cohort
with outcome
Unexposed
Onset
of study
without
outcome
Time
Direction of inquiry
Q: What will happen?
28
Prospective Cohort Study





Appropriate for frequent disease
Can examine only few risk factors
Usually expensive
RR = ‘relative risk’ = incidence rate ratio
AR = incidence difference
29
Case-Control Studies
30
Case-Control Study (1)

Retrospective



First identify cases
Then identify suitable controls


Can use hospital or health register data
Hardest part: who is suitable ??
Then inquire or retrieve previous exposure
By interview
 By databases (e.g. hospital, health insurance)

31
Case-Control Study (2)


Diseased and non-diseased individuals are selected
first
Then past exposure status is retrieved
n
exposed ?
exposed ?
past
yes disease
no
present
future
32
Case-Control Study (3)





Good for rare disease (e.g. cancer)
Can study many risk factors at the same time
Usually low cost
Confounding likely
OR (not RR !!)
33
Case-Control Study Design
Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
Data
collection
Time
Direction of inquiry
Q: What happened?
34
Case-Control study (4)
•
•
•
•
•
Study subjects selected on basis of whether
they have (case) or do not have (control) a
disease
Useful for disease with long latency period
Efficient in terms of time & costs
Particularly suited for rare diseases
Examines multiple exposures to a single
disease
35
Case-control study (5)
Limitations:
(1) susceptible to bias (particularly selection &
recall)
(2) difficulties in selection of controls
(3) ascertainment of disease & exposure status
(4) inefficient for rare exposures unless
attributable risk is high
36
Case Selection
• Define source population
• Cases
– incident/prevalent
– diagnostic criteria (sensitivity + specificity)
• Controls
– selected from same population as cases
– select independent of exposure status
37
Control Selection
• Random selection from source population
• Hospital based controls:
– convenient selection
– controls from variety of diagnostic groups other
than case diagnosis
– avoid selection of diagnoses related to
particular risk factors
– limit number of diagnoses in individuals
38
Summary of Observational Studies
Characteristic
Sampling
Time
Causality
Frequency
measure
Risk
parameter
Cross Sectional
Case Control
Cohort
Random sample: Purposive sample:
population
diseased/nondiseased
One point
Retrospective
Statistical
Screening for
association
many risk factors
Prevalence
None
Purposive sample:
Exposed/nonexposed
Prospective
Testing one (or
few) risk factors
Incidence
Prevalence (risk) Odds ratio
ratio, odds ratio
Relative risk, odds
ratio
39
Clinical Trials
40
Clinical Trials – Drug Development
Basic
Research
In-Vitro
Screening
In-Vivo
Screening
Isolated cells
& tissues
Drug
Licensing
& Release
Clinical
Trials I - III
Safety
Testing
In Humans
41
In Animals
Novel
Compounds
Clinical trials in drug development
(Any alternatives)
In-Vitro Tests Can Show Whether:
• A compound has the desired effect on isolated cells or
tissues
• There are adverse effects on those tissues
• In-Vitro Tests Cannot Show Whether:
• The desired effect will occur in a complete living system
• There will be any adverse effects in a complete living system
42
Clinical trials in drug development
(Any alternatives)

Animal Tests Can:
Suggest which drugs are likely to be effective in
humans
 Indicate which drugs may not be harmful in humans


Animal Tests Cannot:

Predict with absolute certainty what will happen in
humans
43
Clinical trial vs. Cross-sectional

Clinical trial:





Individuals selected by
entry condition
Control over exposure
Exposure groups fully
comparable
Outcome measured after
allocating individuals to
exposure
Therefore: causal
association likely

Cross Sectional Study:




Individuals selected
randomly
Exposure observed as
occurring in nature (groups
not ‘identical’)
Exposure AND outcome
measured at one point in
time
No causal interpretation
44
Clinical Trials-Phases

Phase I - Does it hurt the Patient?


Phase II - Does it help the Patient?


On patients to confirm the effectiveness of the drug
Phase III - Is it any better?


Usually in normal volunteers, small groups for safety testing
Large groups of patients for statistical confirmation of effect
and incidence of side-effects
Phase IV - Does it work in the community?

Post marketing studies. Fine tuning and new rare findings from a
very large population
45
Clinical Trial: Study Design


Uncontrolled
Controlled
Before/after (cross-over)
 Historical
 Concurrent, not randomized
 Randomized

46
Non-randomized Trials
May Be Appropriate
• Early studies of new and untried therapies
• Uncontrolled early phase studies where the
standard is relatively ineffective
• Investigations which cannot be done within the
current climate of controversy
• Truly dramatic response
47
Advantages of Randomized
Control Clinical Trial
1.
Randomization "tends" to produce comparable groups
2.
Assure causal relationship
3.
Randomization produces valid statistical tests
48
Disadvantages of
Randomized Control Clinical Trial
1. Generalizable Results?
 Participants studied may not represent general
study population.
2. Recruitment
 Hard
3. Acceptability of Randomization Process
 Some physicians will refuse
 Some participants will refuse
4. Administrative Complexity
49
Clinical Protocol (1)

Background/Justification
--Where we are in the field
--What the study will add that is important

Objectives
--Primary hypothesis
--Secondary hypotheses
--Other
50
Study Population
Subset of the general population determined by the
eligibility criteria
General population
Eligibility criteria
Study population
Enrollment
Study sample
Observed
51
Clinical Protocol (2)

Study Design and Methods





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Type of study, comparison
Inclusion and exclusion criteria
Description of intervention (what, how)
Concomitant therapy
Examination procedures (baseline, follow-up, outcome
assessment)
Intervention assignment procedure
Data collection sheet
Informed consent
52
Eligibility Criteria
(inclusion & exclusion)


State in advance
Consider
Potential for effect of intervention
 Ability to detect that effect
 Safety
 Ability for informed consent

53
Method Outlines (1)


The independent (predictor) and dependent (outcome)
variables in the study should be clearly identified, defined,
and Measured?
How to choose subjects?








Random or not
Are they going to be representative of the population?
Random selection is not random assignment
Types of Blinding (Masking) Single, Double, Triple.
Control group? How is it chosen?
How are patients followed up? Who are the dropouts?
How is the data quality insured? Reliability?
Consider independent review of data? Compliance?
54
Methods outlines (2)




Reference any unusual methods?
Statistical methods specified in sufficient
details
Is there a statement about sample size issues or
statistical power?
? multicenter study. Quality assurance
measures should be employed to obtain
consistency across sites?
55
Comparing Treatments
• Fundamental principle
• Groups must be alike in all important aspects and only differ in the
intervention each group receives
• In practical terms, “comparable treatment groups” means
“alike on the average”
• Randomization
• Each participant has the same chance of receiving any of the
interventions under study
• Allocation is carried out using a chance mechanism so that neither the
participant nor the investigator will know in advance which will be
assigned
• Blinding
• Avoidance of conscious or subconscious influence
• Fair evaluation of outcomes
56
Patients and Clinicians Kept Blind To
Treatment?
 Investigator
 Care taker
57
Methods outlines (3)

Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria
58
Regular Follow-up

Routine Procedures (report forms)
Interviews
 Examinations
 Laboratory Tests



Adverse Event Detection/Reporting
Quality Assurance
59
Compliance/adherence

Pill counts and computers

Diaries

Biological tests
60
Lipid lowering drugs after myocardial
infarction
Mortality
clofibrate
18.2%
placebo
19.4%
Overall
Clofibrate
18.2%
Clofibrate Adherence
 80
< 80%
15.0%
24.6%
61
Methods outlines (4)

Statistics
--Sample size
--Stopping guidelines
--Analysis plans

Participant protection issues
62
Sample Size




The study is an experiment in people
Need enough participants to answer the
question
Should not enroll more than needed to answer
the question
Sample size is an estimate, using guidelines and
assumptions
63
Contingency Plans




Patient management
Evaluation and reporting to all relevant persons
and groups
Data monitoring plans
Protocol amendment or study termination
64
Human Subjects Protection
•
•
•
•
•
•
•
Institutional Review Board
Informed consent
Different levels of risk
Confidentiality as well as risk of new tx
Patient can refuse to participate w/o effect
Path to exit study known
Compensation
65
Summary





Selection of design should be made on the basis of the
particular hypothesis to be tested with consideration of
current state of knowledge
Consider available resources when deciding on a study
design
A clear and organized study design leads to successful
results
Observational studies are especially valuable in
epidemiology
Clinical trials carry the highest level of evidence and
should be pursued whenever feasible
66