clinical trial designs

study design

1. Trial Designs
Protocol Writing

2. 2
Research is to see what
everybody else has seen, and to
think what nobody else has
thought.
Albert Szent-Gyorgyi
Definitions of Research

3. Research Designs
Observational Studies
Where the exposure or assignment of subjects into
a treated or control groups is beyond the scope of
the investigator.
Interventional Study
Where exposure and allotment of subjects into
treated and control groups is controlled by the
investigator.
2/11/2020 3

4. 4
Where to Start?
A good clinical study starts with
a good questionbased on good hypothesisthat is based on
good and comprehensive reviewof the available evidence
from pre-clinical and clinical data
Type of design depends on the question to be
answered

5. 5
Formulating a Research Question
Focused and specific
What is the prevalence of Hepatitis B surface
Antigen in India?
Cross-sectional study
What are the risk factors for hepatitis B infection?
Prospective cohort or case-control
Is interferon a useful therapy for hepatitis B
infection?
Therapeutic clinical trial

6. 6
Objectives
Specific aims
Clear and detailed
End point(s)
Primary
The main answer to the research question
Secondary
Answer other related questions

7. 7
Observational studyClinical trial
exposed
non exposed
outcome
Clinical
Trial
observational
studydescribe as
occurring in nature
allocate
randomly
Ethics!

8. 8
Important issues in Study Design
Validity: Truth
External Validity:
Can the study be generalized to the population
Internal Validity:
Results will not be due to chance, bias or
confounding factors
Symmetry Principle: Groups are similar

9. 9
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
Important issues in Study Design

10. 10
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?

11. 11
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

12. 12
Clinical Study Types
Observational Studies
Cohort (Incidence, Longitudinal)
Case-Control
Cross-Sectional (Prevalence)
Case Series
Case Report
Experimental Studies
Uncontrolled Trials
Controlled Trials

13. 13
Types of observational studies
Cross -sectional study
Cohort study
Case control study
Case series/case reports

14. 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. 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. 16
Cross -Sectional Study

17. 17
Cross -Sectional Study
Exposure and disease measured once, i.e. at the same
point in time
present futurepast
n
exposed ?
diseased ?

18. 18
Cross-Sectional: Pediatrician-to-Child Ratio
Greg et al. (2001) Pediatrics.107(2):e180
5
10
15
20
25
30
35
40
Pediatricians per
1000 Children
Rural Urban
1981
1986
1991
1996

19. 19
Cohort Studies

20. 20
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 allsubjects
at another point in time.
Typically prospective but can be retrospective,
depending on temporal relationship between study
initiation & occurrence of disease.

21. 21
Cohort Study (1)
Individuals selected by exposure status and future
occurrence of disease measured
present futurepast
n
Exposed
yes
no
disease ?
disease ?

22. 22
Cohort studies (2)
More clearly establish temporal sequence
between exposure & disease
Allows direct measurement of incidence
Examines multiple effects of a single exposure
(nurses’ health study, OC and breast, ovarian
cancers)

23. 23
Cohort studies (3)
Limitations:
time consuming and expensive
loss to follow-up & unavailability of data
potential confounding factors
inefficient for rare diseases

24. 24
Prospective Cohort Study
without
outcome
Cohort
with outcome
with outcome
without
outcome
Exposed
Unexposed
Time
Onset
of study Direction of inquiry
Q: What will happen?

25. 25
Case-Control Studies

26. 26
Case-Control Study (1)
Retrospective
Can use hospital or health register data
First identify cases
Then identify suitable controls
Hardest part: who is suitable ??
Then inquire or retrieve previous exposure
By interview
By databases (e.g. hospital, health insurance)

27. 27
Case-Control Study (2)
Diseased and non-diseased individuals are selected
first
Then past exposure status is retrieved
present futurepast
n
yes
no
disease
exposed ?
exposed ?

28. 28
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 !!)

29. 29
Case-Control Study Design
Cases
Controls
Exposed
Unexposed
Exposed
Unexposed
Time
Data
collection
Direction of inquiry
Q: What happened?

30. 30
•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
Case-Control study (4)

31. 31
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

32. 32
Case Selection
•Define source population
•Cases
–incident/prevalent
–diagnostic criteria (sensitivity + specificity)
•Controls
–selected from same population as cases
–select independent of exposure status

33. 33
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

34. 34
Characteristic

Cross -
Sectional

Case Control

Cohort

Sampling

Random sample:
population

Purposive sample:
diseased/non-
diseased

Purposive sample:
Exposed/non-
exposed
Time One point Retrospective Prospective
Causality Statistical
association
Screening for
many risk factors
Testing one (or
few) risk factors
Frequency
measure
Prevalence None Incidence
Risk
parameter
Prevalence (risk)
ratio, odds ratio
Odds ratio Relative risk, odds
ratio

Summary of Observational Studies

35. 35
Clinical Trials

36. 36
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
Clinical trials in drug development
(Any alternatives)

37. 37
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

38. Parallel Study
38
Treatment A
Treatment B
Outcomes

39. Crossover Study
39
Treatment ATreatment B
Outcome 1
Treatment A Treatment B
Outcome 2

40. 40
Clinical Trial: Study Design
Uncontrolled
Controlled
Before/after (cross-over)
Historical
Concurrent, not randomized
Randomized

41. 41
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

42. 42
Advantages of Randomized
Control Clinical Trial
1.Randomization "tends" to produce comparable groups
2.Assure causal relationship
3.Randomization produces valid statistical tests

43. 43
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

44. 44
Study Population
Subset of the general population determined by the
eligibility criteria
General population
Eligibility criteria
Study population
Enrollment
Study sample
Observed

45. 45
Eligibility Criteria
(inclusion & exclusion)
State in advance
Consider
Potential for effect of intervention
Ability to detect that effect
Safety
Ability for informed consent

46. 46
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?

47. 47
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?

48. 48
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

49. 49
Patients and Clinicians Kept Blind To
Treatment?
Investigator
Care taker

50. When to Unblind
1. Following an SAE
2. When treatment of an SAE depends upon the
treatment received in trial
3. Actually very few situations require unblinding
4. Physicians feel very uncomfortable when blind
procedures are done
50

51. Randomization
To reduce allotment bias
Static Randomization
Stratified Randomization
Block Randomization
Co-variateadaptive randomization
Response adaptive randomization
51

52. 52
Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria
Methods outlines (3)

53. 53
Regular Follow-up
Routine Procedures (report forms)
Interviews
Examinations
Laboratory Tests
Adverse Event Detection/Reporting
Quality Assurance

54. 54
Compliance/adherence
Pill counts and computers
Diaries
Biological tests

55. 55
Statistics
--Sample size
--Stopping guidelines
--Analysis plans
Participant protection issues
Methods outlines (4)

56. 56
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

57. 57
Contingency Plans
Patient management
Evaluation and reporting to all relevant persons
and groups
Data monitoring plans
Protocol amendment or study termination

58. 58
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

59. 59
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