1. Clinical Study: Design and Methods
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
King Faisal Specialist Hospital & Research Centre

2. 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)

3. 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

4. Formulating a Research Question
Focused and specific
What is the prevalence of Hepatitis B surface Antigen in Saudi Arabia? 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
Supported by available data
Is vancomycin better than ceftazidime against gram negative organisms?
Not a replication of already established evidence
Is smoking associated with lung cancer?
Ethical
Answerable
Methods, resources ….etc

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

6. Study Design Your question Your resources Community Describe Analyze
Retrospective
Prospective
Community
Acceptance of research
Observational
Interventional

7. Clinical Study Types Observational Studies Experimental Studies
Cohort (Incidence, Longitudinal)
Case-Control
Cross-Sectional (Prevalence)
Case Series
Case Report
Experimental Studies
Uncontrolled Trials
Controlled Trials
Assignment of individuals is randomized
RCT: Individuals similar at the beginning
RCOT: Prospective analytical, susceptible to bias if carry over effects occur
Observational: allocation or assignement is not under investigator control; weaker potential evidence; potential for large confounding variables
Cohort: prospective, follow-up period to determine effect of exposure and outcome, stronger than case-control but more expensive
Case-Control: retrospective, secondary data from chart review, useful for rare conditions, inexpensive, many forms of bias
Cross-Sectional: descriptive study of relationship between factors at one point in time
Case-Series: series of cases, lack of comparability, source of hypothesis, most common study type
Case-Report: anecdotal evidence,

8. Levels of Evidence
Hierarchy of Strength of Evidence for Treatment Decisions
Level I: N of 1 randomized trial (double-blinded, cross-over)
Level I (A): Systematic reviews of randomized trials
Level I (B): Single randomized trial
Level II (A): Systematic review of observational studies addressing
patient-important outcome
Level II (B): Single observational study addressing important outcome
Level III: Physiologic studies
Level IV: Unsystematic clinical observations (case-reports, anecdotal)
JAMA 2000; 284(10):

9. Observational study  Clinical trial
describe as
occurring in nature
allocate
randomly
exposed
non exposed
outcome
Ethics!
Clinical
Trial

10. 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

11. 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

12. 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?

13. 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

14. Types of observational studies
CROSS - SECTIONAL STUDY
COHORT STUDY
CASE CONTROL STUDY
CASE SERIES/CASE REPORTS

15. 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

16. 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

17. Cross - Sectional Study

18. Cross - Sectional Study (1)
Exposure and disease measured once, i.e. at the same point in time n
exposed ?
diseased ?
present
future
past

19. 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
In class: association between hair color and hair dyeing

20. 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
In class: association between hair color and hair dyeing

21. Cross-Sectional: Pediatrician-to-Child Ratio
Greg et al. (2001) Pediatrics.107(2):e18

22. Cross-Sectional: Risk Factors for Smoking
Variable OR
95% CI
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
36.5
18.4
7.5
2.1
9.3 – 142.8
5.5 – 61.8
2.2 – 26.0
0.6 – 7.9
Any siblings who smoke: Y vs. N
2.8
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

23. Cohort Studies

24. 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.

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

26. 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)

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

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

29. Prospective Cohort Study
Appropriate for frequent disease
Can examine only few risk factors
Usually expensive
RR = ‘relative risk’ = incidence rate ratio
AR = incidence difference
Cohort study in class: risk of sex on starting smoking during the BMLS study

30. Case-Control Studies

31. Case-Control Study (1) Retrospective First identify cases
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)

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

33. 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 !!)
Case control in class: effect of having more than one sibling on piercing

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

35. 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

36. 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

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

38. 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

39. Summary of Observational Studies

40. Clinical Trials

41. Clinical Trials – Drug Development
Basic
Research
Novel
Compounds
In-Vitro
Screening
Isolated cells
& tissues
In-Vivo
Screening
In Animals
Safety
Testing
Drug
Licensing
& Release
Clinical
Trials I - III
In Humans

42. 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

43. 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

44. Clinical trial vs. Cross-sectional
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
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

45. Clinical Trials-Phases
Phase I - Does it hurt the Patient?
Usually in normal volunteers, small groups for safety testing
Phase II - Does it help the Patient?
On patients to confirm the effectiveness of the drug
Phase III - Is it any better?
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

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

47. 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

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

49. 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

50. Clinical Protocol (1) Background/Justification Objectives
--Where we are in the field
--What the study will add that is important
Objectives
--Primary hypothesis
--Secondary hypotheses
--Other

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

52. Clinical Protocol (2) Study Design and Methods
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

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

54. 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?

55. 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?

56. 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

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

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

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

60. Compliance/adherence
Pill counts and computers
Diaries
Biological tests

61. Lipid lowering drugs after myocardial infarction
Mortality
clofibrate 18.2%
placebo 19.4%
Clofibrate Adherence
 < 80%
18.2% % %
Overall
Clofibrate

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

63. 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

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

65. 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

66. 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