Methodologi Clinical Trial
Transcript of Methodologi Clinical Trial
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Clinical Study: Designand Methods
Hail M. Al-Abdely, MD
Consultant, Infectious Diseases
King Faisal Specialist Hospital & ResearchCentre
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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 ofcritical investigation.
(The Concise Oxford Dictionary)
Definitions of Research
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Where to Start?
A good clinical study starts with
a good questionbased ongood hypothesisthat is based ongood and comprehensive reviewof the available evidence
from pre-clinical and clinical data
Type of design depends on the question to beanswered
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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
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Objectives
Specific aims
Clear and detailed
End point(s) Primary
The main answer to the research question
Secondary
Answer other related questions
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Study Design
Your question
Describe
Analyze
Your resources Retrospective
Prospective
Community Acceptance of research
Observational
Interventional
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Clinical Study Types
Observational Studies Cohort (Incidence, Longitudinal)
Case-Control Cross-Sectional (Prevalence)
Case Series
Case Report
Experimental Studies Uncontrolled Trials
Controlled Trials
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Level I: N of 1 randomized trial (double-blinded, cross-over)
Level I (A): Systematic reviews of randomized trials
Level I (B): Single randomized trialLevel 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)
Levels of Evidence
Hierarchy of Strength of Evidence for Treatment Decisions
JAMA 2000; 284(10):1290-96
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Observational study Clinical trial
exposed
non exposed
outcome
Clinical
Trial
observational
studydescribe as
occurring in nature
allocate
randomlyEthics!
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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
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Confounding:distortion of the effect of one risk factor by the presence ofanother
Bias:Any effect from design, execution, & interpretation that shifts orinfluences results
Confounding bias:failure to account for the effect of one or morevariables that are not distributed equally
Measurement bias:measurement methods differ between groups
Sampling (selection) bias:design and execution errors insampling
Important issues in Study Design
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IntroductionWhy 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?
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Why doing a study?
Alternative:
census: test every individual in the population
use available data, e.g. hospitalsBut:
- data availability
- data quality
- cost
- questions require specific type of data and
circumstances
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Types of observational studies
CROSS - SECTIONAL STUDY
COHORT STUDY
CASE CONTROL STUDY
CASE SERIES/CASE REPORTS
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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
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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
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Cross - Sectional Study
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Cross - Sectional Study (1)
Exposure and disease measured once, i.e. at the samepoint in time
present futurepast
n
exposed ?
diseased ?
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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
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Cross - Sectional Study (3)
Can study several exposure factors and outcomessimultaneously
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
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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
18.47.5
2.1
9.3142.8
5.561.82.226.0
0.67.9
Any siblings who smoke: Y vs. N 2.8 1.84.3
Mother smokes:
Yes vs. No
Have no mother vs No
1.9
3.5
1.32.9
0.815.0
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Cohort Studies
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Cohort studies
Follow-up studies; subjects selected on presence orabsence of exposure & absence of disease at onepoint in time. Disease is then assessed for allsubjects
at another point in time.
Typically prospective but can be retrospective,depending on temporal relationship between studyinitiation & occurrence of disease.
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Cohort Study (1)
Individuals selected by exposure status and futureoccurrence of disease measured
present futurepast
n
Exposed yesno
disease ?disease ?
n
Exposed yesno
disease ?disease ?
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Cohort studies (2)
More clearly established temporal sequencebetween exposure & disease
Allows direct measurement of incidence
Examines multiple effects of a single exposure(nurses health study, OC and breast, ovarioan
cancers)
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Cohort studies (3)
Limitations:
time consuming and expensive
loss to follow-up & unavailability of data potential confounding factors
inefficient for rare diseases
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Prospective Cohort Study
without
outcome
Cohort
with outcome
with outcome
without
outcome
Exposed
Unexposed
TimeOnset
of study Direction of inquiry
Q: What will happen?
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Prospective Cohort Study
Appropriate for frequent disease
Can examine only few risk factors
Usually expensive
RR = relative risk = incidence rate ratio
AR = incidence difference
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Case-Control Studies
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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)
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Case-Control Study (2)
Diseased and non-diseased individuals are selectedfirst
Then past exposure status is retrieved
present futurepast
n
yes
nodisease
exposed ?
exposed ?
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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 !!)
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Case-Control Study Design
Cases
Controls
Exposed
Unexposed
Exposed
Unexposed
TimeDatacollection
Direction of inquiry
Q: What happened?
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Study subjects selected on basis of whetherthey have (case) or do not have (control) adisease
Useful for disease with long latency period Efficient in terms of time & costs
Particularly suited for rare diseases
Examines multiple exposures to a singledisease
Case-Control study (4)
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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 unlessattributable risk is high
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Case Selection
Define source population
Cases
incident/prevalentdiagnostic criteria (sensitivity + specificity)
Controls
selected from same population as casesselect independent of exposure status
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Control Selection
Random selection from source population
Hospital based controls:
convenient selectioncontrols from variety of diagnostic groups other
than case diagnosis
avoid selection of diagnoses related toparticular risk factors
limit number of diagnoses in individuals
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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
Frequencymeasure Prevalence None Incidence
Risk
parameter
Prevalence (risk)ratio, odds ratio
Odds ratio Relative risk, oddsratio
Summary of Observational Studies
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Clinical Trials
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Clinical Trials Drug Development
Basic
ResearchNovel
Compounds
SafetyTesting
Drug
Licensing
& Release
In-Vitro
ScreeningIsolated cells
& tissues
In-Vivo
ScreeningInAnimals
ClinicalTrials I - III
In Humans
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Clinical trials in drug development(Any alternatives)
In-Vitro Tests CanShow Whether:
A compound has the desired effect on isolated cells ortissues
There are adverse effects on those tissues
In-Vitro Tests CannotShow Whether:
The desired effect will occur in a complete living system
There will be any adverse effects in a complete living system
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Animal Tests Can:
Suggest which drugs are likely to be effective inhumans
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)
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Clinical trial vs. Cross-sectional
Clinical trial: Individuals selected by
entry condition
Control over exposure
Exposure groups fullycomparable
Outcome measured afterallocating individuals to
exposure Therefore: causal
association likely
Cross Sectional Study: Individuals selected
randomly
Exposure observed as
occurring in nature (groupsnot identical)
Exposure AND outcomemeasured at one point in
time No causal interpretation
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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
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Clinical Trial: Study Design
Uncontrolled
Controlled
Before/after (cross-over)
Historical
Concurrent, not randomized
Randomized
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Non-randomized TrialsMay Be Appropriate
Early studies of new and untried therapies
Uncontrolled early phase studies where thestandard is relatively ineffective
Investigations which cannot be done within the
current climate of controversy
Truly dramatic response
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Advantages of Randomized
Control Clinical Trial
1. Randomization "tends" to produce comparable groups
2. Assure causal relationship
3. Randomization produces valid statistical tests
Di d f
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Disadvantages of
Randomized Control Clinical Trial
1. Generalizable Results?
Participants studied may not represent generalstudy population.
2. Recruitment
Hard
3. Acceptability of Randomization Process
Some physicians will refuse Some participants will refuse
4. Administrative Complexity
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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
Study Population
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Study Population
Subset of the general population determined by the
eligibility criteria
General population
Eligibility criteria
Study population
Enrollment
Study sampleObserved
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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, outcomeassessment)
Intervention assignment procedure Data collection sheet
Informed consent
Eli ibilit C it i
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Eligibility Criteria(inclusion & exclusion)
State in advance
Consider
Potential for effect of intervention
Ability to detect that effect
Safety
Ability for informed consent
M h d O li (1)
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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?
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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?
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Comparing Treatments Fundamental principle
Groups must be alike in all important aspects and only differ in theintervention 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
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Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria
Methods outlines (3)
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Regular Follow-up
Routine Procedures (report forms)
Interviews
Examinations
Laboratory Tests
Adverse Event Detection/Reporting
Quality Assurance
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Compliance/adherence
Pill counts and computers
Diaries
Biological tests
Lipid lowering drugs after myocardial
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Lipid lowering drugs after myocardial
infarction
Mortality
clofibrate 18.2%
placebo 19.4%
ClofibrateAdherence
80 < 80%
18.2% 15.0% 24.6%
Overall
Clofibrate
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Statistics
--Sample size
--Stopping guidelines
--Analysis plans
Participant protection issues
Methods outlines (4)
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Sample Size
The study is an experiment in people
Need enough participants to answer thequestion
Should not enroll more than needed to answerthe question
Sample size is an estimate, using guidelines andassumptions
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Contingency Plans
Patient management
Evaluation and reporting to all relevant personsand groups
Data monitoring plans
Protocol amendment or study termination
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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
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Summary
Selection of design should be made on the basis of theparticular hypothesis to be tested with consideration ofcurrent 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