Clinical Trial Designs and Evaluation (5&6) Flashcards
Design Issues
- Primary Question
- Study population
- Randomization
- Blinding
- Control Groups
Every clinical trial has to have a ____ ____. This as well as secondary questions should be selected carefully an clearly defined and stated.
Primary Question (can be put into a statement)
Examples of Primary and Secondary questions
The outcome may be a clinical event such as improving survival, ameliorating an illness or disease complications, reducing symptoms, or improving quality of life
Modifying an intermediate or surrogate characteristic such as blood pressure; or changing a biomarker such as a laboratory value.
Study population
should be defined in advance, stating unambiguous inclusion and exclusion (eligibility) criteria.
The study population is the _____ of the population with the condition or characteristics of interest defined by the eligibility criteria.
subset
The trial participants are selected from
the study population.
Eligibility for study population
relate to participant safety and anticipated effect of the intervention.
People are chosen (in study population design issue) for whom there is a high likelihood of _____ ____ _____ ___ _ ___ ___ .
Careful choice will allow for detection of results in a reasonable period of time, given a reasonable number of participants and a finite amount of funding.
detecting the hypothesized effects of the intervention.
Randomized controlled trials (RCTs)
are comparative studies with an intervention group and a control group.
The randomization procedure ______ assigns the participant to one group or the other.
randomly
Random assignment to treatment is only ethical when there is genuine ____ _____ _______ ______ ___ ____ ____ __ ______
uncertainty on the part of the relevant expert community about which therapy is most effective for a given condition (“clinical equipoise”).
Clinical equipois
Uncertainty on the part of the relevant expert community about which therapy is most effective for a given condition
RCTS are only given under this condition
Advantages of Randomization:
- Removal of bias
- Comparable groups
- Statistical validity
Randomization ____ potential bias in allocating participants to groups
removes
Selection bias is
due to bias
Bias can easily occur in a ___ ______ ______ because the investigator or the participant may influence the choice of intervention.
non-randomized study
This influence of bias can be _____ or ________and can be due to numerous factors, including the prognosis of the participant.
conscious or subconscious
Bias
Can easily invalidate the trial results.
Comparable groups
Groups that are the same in both known and unknown characteristics
Randomization results in groups that are the same for important characteristics (known and unknown).
In comparable groups we can say the groups being compared tend to be
“evenly balanced.”
An advantage of randomization results in statistical validity
The validity of statistical tests of significance is guaranteed.
If randomization is not used, further assumptions about the comparability of the groups and the appropriateness of the ____________ must be made before the comparisons will be valid.
statistical models
Non randomized clinical trials
Establishing the validity of these assumptions may be difficult.
Non-Randomized Control Studies
Participants are allocated to one of two (or more) groups, but the allocation is not a random process.
Non-Randomized Control Studies Examples
- Surgery vs Medical clinical
2. Patient offered two treatments and chooses
The major weakness of non-randomized control studies is the potential that the
intervention group and control group are not strictly comparable (bias).
(We lost comparability and Statistical validity as as well as bias)
In non randomized control studies, comparisons between groups ___ __ ____, using statistical techniques to adjust for observed baseline imbalances. __ ______ ______ ______
Can be made
Regardless, bias is difficult to overcome.
Randomization in review
tends to produce study groups comparable with respect to known as well as unknown risk factors, removes investigator bias in the allocation of participants and ensures statistical validity.
Bias can be caused by
conscious factors, subconscious factors, or both.
One solution to the problem of bias is to
keep the participants and the investigators blinded, or masked, to the identity of the assigned intervention.
Single-Blind:
Only the participants are unaware of the treatment (or placebo) they are receiving.
Double-Blind:
Neither the participants nor the investigators know the identity of the intervention assigned.
Ideally, trials should be _____-______ in order to limit potential problems of bias during data collection and assessment.
double-blinded
Numerous steps must be taken to maintain the blind,
like:
e.g., identical tablet appearance and taste, coding of drugs bottles, identical treatment administration.
For some trials, e.g., many surgery trials, blinding is __ ______.
not feasible.
Sound scientific clinical investigation almost always demands that a _____ _____ be used against which the new intervention can be compared.
control group
Randomization is the preferred way of
assigning participants to control and intervention groups.
Most trials use the so-called
parallel design or concurrent control
Parallel design
the intervention and control groups are followed simultaneously from the time of allocation to one or the other (concurrent control).
Historical control studies
these compare a group of participants on a new intervention with a previous group of participants on standard or control therapy.
Concurrent (Parallel) Control Studies
When both the control and the intervention are doing it at the same time
Types of Concurrent (Parallel) Control Studies
- Cross-over trial (each person is part of both the intervention and control)
- Withdrawal study, in which everyone is first on the intervention then half and half
(Parallel Control Study)
Participants in the control group may be on
placebo, no treatment, usual or standard-of-care, or a specified treatment.
Principal difference between placebo and no treatment is that a no-treatment trial is
not blinded.
if there is no placebo they know they are receiving nothing thus not blinded
Cross-over trial (type of parallel control study)
uses each participant at least twice, at least once as a member of the control group and at least once as a member of one or more intervention groups.
Withdrawal study (type of parallel control study)
This one is randomized
starts with all participants on the active intervention and then, usually randomly, assigns a portion to be followed on the active intervention and the remainder to be followed off the intervention.
A placebo is an
inactive substance or intervention, such as an inactive tablet or sham surgery, that resembles the comparable active substance or intervention.
A new intervention is added to ____ or _______ and compared against that care plus placebo.
usual care or standard-of-care and compared against that care
PLUS PLACEBO
A placebo ___ ___ ____ ______ if an existing therapy has been proven beneficial (standard-of-care).
may not be considered ethical
Placebo is not always feasible
especially for some surgery and oncology trials
Placebo effect
The simple act of receiving a treatment (active or not) may, in itself, be efficacious because of an expectation of benefit.
The placebo effect is a potential confounder in assessing the efficacy of any therapeutic intervention.
Failed Blinding with Placebo
A trial at the National Institutes of Health of the possible benefits of ascorbic acid vs. placebo for the common cold was designed as a double-blind study.
Those in placebo dropped out
Those who knew they were on Ascorbic reported better
Those who didn’t know did not change
Cross-Over Designs
each participant receives either intervention or control (A or B) in the first period and the alternative in the succeeding period.
(In Cross over designs)
Each participant serves as his or her own .
control
(In Cross over designs)
The order in which A and B are given to each participant is ______.
randomized
Thus, approximately half of the participants receive the intervention in the sequence AB and the other half in the sequence BA.
Fairly strict assumption must be made about cross over designs:
effects of intervention during first period must not carry over into second period. Often can’t be made.
(In Cross over designs)
May require ___________ between periods.
“wash-out”
Withdrawal Studies
Participants on a particular treatment (e.g., for a chronic disease) are taken off therapy or have the dosage reduced.
(In withdrawal studies)
Objective of these studies is to _____ _______ __ _________ __ _____ _______
assess response to discontinuation or dose reduction.
(In withdrawal studies)
This design may be validly used to evaluate the _______ of benefit of an intervention already known to be useful.
duration
In historical control studies
a new intervention is used in a series of participants and the results are compared to the outcome in a previous series of comparable participants (e.g., data retrieved from a database).
Historical controls are, by definition, ___________.
nonrandomized
The argument for using a historical control design is that
all new participants can receive the new intervention. Many clinicians believe that all participants should have the possibility of receiving a new therapy.
Historical control studies are particularly vulnerable to _____.
bias
An improvement in outcome for a given disease may be attributed to a new intervention when, in fact, the improvement may stem from
a change in the patient population or patient management.
HCTs (79%) and RCTs (20%)
more bias in finding better results of with historical control studies
Shown to be harmful through the use of RCTs
High-dose oxygen therapy in neonates
Antiarrhythmic drugs after myocardial infarction
Fluoride treatment for osteoporosis
Bed rest in twin pregnancy
Hormone replacement therapy in vascular prevention
Extracranial to intracranial arterial bypass surgery in stroke prevention
High-dose aspirin for carotid endarterectomy
Shown to be beneficial through the use of RCTs
β blockers in heart failure
Digoxin after myocardial infarction
For each clinical trial, a _______ _______ should be carefully selected, clearly defined, and stated in advance.
The _____ ______should be defined in advance, stating unambiguous inclusion and exclusion (eligibility) criteria.
primary question
study population
