Transcript Health and Human Services Disaster Preparedness Initiative

RCT Design
Randomized Controlled Clinical
Trial
Types of Reserech
1. Qualitative
2. Quantitative
Quantitative methods
(epidemiological studies)
Observational
Experimental
or
Interventional
Interventional
• Lab experiment
• Clinical Trial
• Quasi-experimental
Cohort study
Time
Onset of
study
Disease
Exposed
No Disease
Population
Disease
Unexposed
No Disease
Modified from Greenberg et al 2001
Direction of enquiry
RCT
Time
Onset of
study
Disease
Treatment
No Disease
Eligible
Patients
Randomize
Disease
Placebo
No Disease
Direction of enquiry
Clinical Trial: Definition
A clinical trial is a prospective study
comparing the effect and value of
intervention(s) against a control in
human beings.
‫دادگاه رسیدگی به اتهام دارو‬
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‫متهم‪ :‬دارو‬
‫اتهام ‪ :‬من از بقیه بهترم!‬
‫وکیل مدافع‪ :‬پژوهشگر‬
‫دادستان‪ :‬بیمار‬
‫قاضی ‪ :‬سردبیر مجله‬
‫هیئت منصفه‪ :‬داورهای مقاله‬
Key Elements of a Clinical Trial
1.
2.
3.
4.
5.
6.
7.
Selection of subjects
Allocation of exposure (Randomization)
Blinding
Types of control
Data collection
Statistical issues
Ethical considerations
1) Selection of subjects
• Study population
• All patients with the disease/
condition/characteristic of interest who
meet the entry criteria
• Study sample
• Those patients from the study
population that were recruited and
chose to enroll.
General Design of Clinical Trial
Intervention
PAR
S
PAR =
S
=
R
=
T
=
Study
R
Sample
Outcome
T
No
Intervention
No
Outcome
Population at Risk (Population with condition)
Sampling design (study population)
Randomize intervention
Elapsed time
2) What is randomization
• Scientifically managed chance
• Each participant has the same chance
as the other participant in receiving the
study treatment
General Design of Clinical Trial
Intervention
PAR
S
PAR =
S
=
R
=
T
=
Study
R
Sample
Outcome
T
No
Intervention
No
Outcome
Population at Risk (Population with condition)
Sampling design
Randomize intervention
Elapsed time
Why Randomise
“To eliminate biases that may lead to
systematic differences between
treatment groups” – Altman 1991
Registration/ Randomization
Registration
• Identification of appropriate patients
• Instructions given to all participating
clinicians
• Commitment from clinicians to consider all
relevant patients
• Eligibility check
• Fill out eligibility checklist
Continued 
Registration
(cont’d)
• Informed consent
• Patient (and clinician) must accept
randomization
• Formal entry into the trial
• Baseline study form completed and the
patient is randomized
Randomization
• Tends to produce groups that are comparable
with respect to known and unknown risk
factors
• Prevents allocation bias
• Ensures that statistical tests will be valid
Key point
• The allocation process should be
unpredictable to avoid selection bias
Who randomizes?
When?
How?
Who randomizes
• An independent person (“entity”) should
• Generate the randomization schedule
• Makes treatment assignments
• “Independent person” at a single institution
•
•
•
•
Biostatistician
Data manager
Clinician not involved in patient care
Pharmacist (double-blind trial)
• “Independent entity” in a multi-center trial
• Central coordinating center (phone/computer)
When do you randomize?
• As close as possible to the start
of treatment
How do you randomize?
• Simple randomization
• Block randomization
• Stratified randomization
Continued 
Simple randomization
Methods
• Coin toss (p=0.5 for equal allocation)
• Random number tables
• 01234  A
• 56789  B
• Random number generator (calculator, statistical
software)
• 0.000 – 0.499  A
• 0.500 – 0.999  B
Implications
• On average, equal sized groups
• Possible imbalance (n < 100)
Blocked randomization
Methods
Purpose: to ensure equal-sized groups
For equal allocation, set up treatment blocks of size 2, 4,
6, 8, … with half the elements designated for A and half
for B
Example: Blocks of size 4
AABB ABAB ABBA BBAA BABA BAAB
Randomize order of which block is used.
Repeat as needed.
Stratified randomization
• Assures balance over confounders
• Stratification factors (e.g., age, sex, disease stage,
smoking history) are measured prior to
randomization
• Randomization is performed within stratum (usually
blocked within a stratum)
Example: Breast cancer
Stratum Age # (+) nodes
1
2
3
4
< 50
≥ 50
< 50
≥ 50
1-3
1-3
≥4
≥4
Assignment
ABBA
AABB
BABA
BBAA
BBAA …
BAAB …
BABA …
ABAB …
Importance of Allocation Concealment
(Randomization)
• Unclearly concealed and inadequately
concealed trials, compared to
adequately concealed trials,
exaggerated the estimates of an
intervention’s effectiveness by 30% to
40%, on average
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of
bias: dimensions of methodological quality associated with estimates
of treatment effects in controlled trials. JAMA 1995;273:408-412.
Exclusions After Randomization
• Can introduce bias and should be
carefully scrutinized
• All randomized patients should be
analyzed, and analyzed as part of the
group to which they were initially
assigned
• ITT (Intention-to-treat)
Participants
Randomize
Placebo
40% Noncompliance
60%
Compliance
New Oral Drug
25% Noncompliance
75%
Compliance
Group representing the
policy of no treatment
Group representing the
policy of oral treatment
Outcome
Outcome
Intention-to-treat analysis (ITT)
• A strategy for analyzing data in which all
participants are included in the group to
which they were assigned, whether or
not they completed the intervention
given to the group
Intention-to-treat analysis (ITT)
• Advantage: Corresponds to the one
actually faced by clinicians
• Disadvantage: Increasing the chance
of “no difference”
Explanatory Trials
• Disadvantage: The study no longer
represents a randomized trial, and it is
simply a cohort study
Loss to follow-up
• “With as little as 10% loss to follow-up in
each arm, the chance of obtaining a
false positive result can easily double”
Lachin JM. 2000
3) Blinding
• “The practice of keeping the trial
participants, care providers, those
collecting data, and sometimes even
those analyzing data unaware of which
intervention is being administered to
which participant”
Types of Blinding
• Single Blind: The patient is blind
• Double Blind: The patient and the
investigator are blind
• Triple Blind: The patient, investigator and
analyzer are blind. The statistician can only be
partially blinded since he/she has to know
which patients are in the same treatment
group.
Blinding
• Open studies are more likely to favor
experimental interventions over the
controls
Colditz GA 1989
• Appropriate use of blinding may
decrease overoptimistic estimates of
treatment effect by up to 19%
Juni P et al 2001
Blinding
In some studies blinding is impossible
or very difficult:
Surgery, radiotherapy, diet, organization
of medical care,…
Key Elements of a Clinical Trial
1.
2.
3.
4.
5.
6.
7.
Selection of subjects
Allocation of exposure (Randomization)
Blinding
Types of control
Data collection
Statistical issues
Ethical considerations
Types of Control
1.
2.
3.
4.
Placebo control
No treatment control
Positive control
Historical control
•
Uncontrolled trials
Why control?
• Do Before-after studies need control group?
1. Unpredictable clinical course:
SBE, Rabies, or Bowel infarction rarely
improve without treatment, but most
diseases do not have such predictable
outcomes
For situations which clinical course is very
variable before after studies are unreliable
i.e., BPH
Why control?
2) Nonspecific effects:
There is no way of separating
Hawthorne and placebo effects
3) Regression to the mean:
Normal distribution
4) Predictable improvement:
URI, GE
When Placebo Controls
May be Used
• There is no standard treatment
• Standard treatment has been shown to
be no better than placebo and evidence
causes doubt about therapeutic
advantage of standard therapy
When Placebo Controls May be
Used: Controversial Conditions
• Many argue that persons with
conditions with a low risk of harm
(understand as low probability or low
magnitude of harm) may be entered into
a placebo arm
• Many argue that placebo controls are
ethical when resources are limited and
standard treatment is not available
When Placebo Controls
May be Used
• In a population of patients who are
refractory to standard treatment and for
whom there is no standard second-line
treatment
• Testing add-on treatment to standard
therapy when all subjects in the trial
receive all treatments that would
normally be prescribed
Historical control
Problems:
1. The data obtained from the study groups
must be comparable in kind and quality
2. Many things change over time: supportive
therapy, living condition, nutrition, lifestyle,
…
• When the disease is uniformly fatal the
decline in mortality could be assigned to the
new drug
No treatment group
• A significant difference between placebo
and no treatment in trials with
continuous subjective outcomes may
occur
Clinical Trial Phases
• Phase I: Normal volunteers
• To find Maximum tolerated
dose
• Phase II: Patients with
Disease
• To establish whether there is
any effect and what side
effects
• Phase III: Clinical trial
• Phase IV: Long term
surveillance
Phase IV
Phase III
Phase II
Phase I
Phases of Clinical Trials
Phase I:
Dose-finding trials
Goals
• To assess safety
• To determine the MTD in humans
• To investigate clinical pharmacology
Participants
• Patients who have not improved on
conventional therapy or normal volunteers
Continued 
Phase I:
Dose-finding trials
Methods
• Single arm
• 18-30 patients (variable)
• Escalating doses given to small numbers
of patients
• Stop when risk of adverse events > 50%
or any serious toxicity
Continued 
Phase I:
Dose-finding trials
Primary Design Issue
• To balance conservative dose
escalation against the number of
patients required.
Phase II:
(First look at effectiveness)
Goals
• To begin to assess treatment effect
• To estimate the risk of adverse events
Participants
• Patients who have not improved on
conventional therapy
Continued 
Phase II
(Cont’d)
Methods
• (Usually) single arm
• 25-40 patients (up to 100)
Continued 
Phase II
(Cont’d)
Primary Design Issue
• To maximize the chance of detecting an
active agent
• To minimize the change of declaring an
inactive agent as active
• To enroll as few patients as possible
Phase III:
Comparative trials
Goals
• To determine the efficacy of an
experimental treatment versus a control
(no treatment, placebo, standard therapy)
Participants
• Patients often in better condition than
those participating in Phase I/II trials
Continued 
Phase III:
Comparative trials
Methods
• 2 (or more) arms
• Seldom < 100 patients; often much more
• Treatment assignment is random
• May or may not employ an early stopping
rule..
Continued 
Phase III:
Comparative trials
Primary Design Issues
• To ensure comparability of the treatment
and control groups
• To allow for adequate patient follow-up
• To enroll sufficient numbers of patients so
that meaningful comparisons can be
made
Ethics
• Harm vs. Benefit
• Informed consent
• Confidentiality
CONSORT
• CONsolidated Standards Of
Reporting Trials
Good Clinical Practice
Good Clinical Practice (GCP)
• A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance
that
• the Data and Reported Results are Credible, and
Accurate, and that = Quality Data
• the Rights, Integrity, and Confidentiality of Trial
Subjects are Protected. = Ethics
Quality Data + Ethics = GCPs
The set of international ethical and scientific
quality standards for the design and
conduct of clinical trials is called:
A. Good Manufacturing Practice
B. Good Clinical Practice
C. Good Laboratory Practice
D. Federal regulations
• GCP guidelines are endorsed and followed by
the FDA.
• ICH has developed guidelines that are much
more strict and extensive than FDA
guidelines.
• The International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human
Use (ICH)
Good Clinical Practice - 12 Golden GCP Rules
1. Know and follow the study protocol
2. Select, train and log suitable study personnel
3. Record data carefully
4. Ensure study equipment is adequate
5. Maximise trial patients protection
6. Predict accurately and log patient recruitment
7. Meticulously document product accountability
8. Ensure timely and efficient safety reporting
9. Ensure the quality of lab evaluations
10. Maintain good trial files and archives
11. Maximise data quality
12. Keep everyone fully informed.
The Hierarchy of Evidence
1. Systematic reviews & meta-analyses
2. Randomised controlled trials
3. Cohort studies
4. Case-control studies
5. Cross sectional surveys
6. Case reports
7. Expert opinion
8. Anecdotal
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