Week 11- Interventional Studies Flashcards
OVERALL DIAGRAM
TIMELINE DIAGRAM
What are experimental (intervention) studies?
– Investigator completely controls exposure
* type, amount, duration, and
* who receives it (randomization)
– Can confidently attribute cause and effect due to
prospective designs and the high internal validity of trials
– Trials are not always feasible, appropriate, or ethical
Why is experimental studies regarded as the most scientifically vigorous study design?
- Random assignment reduces confounding bias
- Concealment reduces selection bias
- Blinding reduces biased measurement (information bias)
What are prophylactic trials?
Evaluate efficacy of intervention
designed to prevent disease, e.g., vaccine, vitamin
supplement, patient education
What are treatment trials?
Evaluate efficacy of curative drug or
intervention or a drug designed to manage signs and
symptoms of a disease (e.g., arthritis, hypertension)
What are RCT trials?
Individuals, tightly controlled, narrowly
focused, highly select groups, short or long duration
What are community/ cluster trials?
Cities/regions/schools/hospitals, less rigidly controlled,
long duration, usually primary prevention
How many clinical trial phases are there?
4
What does phase 1 include?
Researchers test a new drug or treatment in
a small group of people for the first time to evaluate
its safety, determine a safe dosage range, and
identify side effects (no control group is included)
What does phase 2 include?
The drug or treatment is given to a larger
group of people to see if it is effective (outcome
assessment) and to further evaluate its safety (no
control group is included)
What does phase 3 include?
The drug or treatment is given to large
groups of people to confirm its effectiveness,
monitor side effects, compare it to commonly used
treatments or placebo, and collect information that
will allow the drug or treatment to be used safely
CONTROL GROUP
What does phase 4 include?
Studies are done after the drug or
treatment has been marketed to gather information
on the drug’s effect in various populations and any
side effects associated with long-term use
What is a randomised controlled trial (RCT)?
- RCT is a study in which participants are assigned to a
study group - Procedures are controlled to ensure that all participants
in all study groups are treated the same except for the
intervention that is unique to their group - Assigned to treatment conditions at random (i.e., they
have an equal probability of being assigned to any
group) - Study groups are also called study arms or treatment
conditions
Why is randomisation important?
- Random assignment ensures that known and
unknown person and environment characteristics that
could affect/distort the outcome of interest are evenly
distributed across groups => control for known and
unknown confounders - Gives the investigator confidence that differences in
outcome between treatment and control were
actually caused by the treatment, since random
assignment (theoretically) equalizes the groups on all
other variables
What does Allocation Concealment mean?
Allocation concealment means that the person who
generates the random assignment remains blind to what
condition the person will enter
Why is allocation concealment important?
If allocation is not concealed, research staff is prone to
assign “better” patients to intervention rather than
control, which can bias the treatment effect upward by
20-30%
What is blinding?
- In blinding, the researchers collecting data are prevented
from knowing certain information about a participant
(e.g., what treatment arm they are in) in order to prevent
this information from affecting how they collect data
What is double-blinding?
- Ideally, to minimize information bias, both the participant
and the investigator should be kept blind to
the participant’s random assignment. That level of
double-blinding may or may not be feasible. - Investigators should implement the greatest level of
blinding that is feasible
What are the 2 types of groups in RCTs?
- Intervention group= receives treatment of interest
- Control group= receives placebo/another treatment
What is a placebo?
A Substances (usually a pill) identical to intervention substance, but LACKS THE ACTIVE INGREDIENTS (chemically inert)
What is the placebo effect?
The placebo effect is a largely beneficial psychological effect of receiving treatment which comes from:
1. Patient’s beneficial response to investigation (incl. response to therapeutic ritual)
2. Patient’s beneficial response to observation and assessment
3. Patient’s beneficial response to patient-doctor interaction
What is the goal of Placebo-controlled trials?
Allows for the study of effectiveness of intervention treatment BEYOND PLACEBO EFFECTS
What is masking of placebo?
The same appearance, size, colour, taste (or even side effects) for active and placebo drug to reduce bias
What are double blind trials?
-This level of blinding reduces the influence of expectations
held by participants or by research staff about which
treatment will have a better effect on the outcome.
-Double-blinding is most feasible for drug trials, in which the
effect of a medication is being compared to a placebo that
looks similar
What else can the control group be except for placebo group?
RCTS can have several intervention groups and may not have a placebo group
1. If new treatment is being compared to old/ conventional treatment (OLD TREATMENT ACTS AS CONTROL)
2. If different dosages of a single treatment is being compared (CONTROL GROUP IS THE LOWEST DOSE)
What is partial blinding?
- Double-blinding is rarely possible in trials of
behavioral treatment. It is usually obvious to
participants which treatment they are receiving but
the assessor of the outcome may be blinded to that
information - Even if the treatment assignment is known by the
research staff who delivers the treatment, the staff
who assess the study outcome can and should be kept
blind to the patient’s treatment condition.
– Special care is needed to prevent staff and study
participants from unblinding the outcome assessor
What are unblinded trials?
- Especially when neither participant nor
investigator can be blinded, it is best if participants
and research staff hold equally positive
expectations about the merits of the treatment
and control conditions.
– The state of equipoise, uncertainty about which
intervention condition will work best, is also the ethical
justification for conducting a trial.
Why is blinding important?
- It is as important as randomization because it prevents
– Biased assessment of outcomes post-randomization
(i.e., measurement or ascertainment bias) - Blinding also helps reduces non-compliance and
contamination - Blinding is particularly important if we have “soft”
outcomes
– e.g., self-report, investigator opinion - Sometimes blinding is not possible (= Open trial). If so,
– Choose a “hard” outcome e.g. levels of CRP, lipids
– Standardize treatments as much as possible - Blinding may be hard to maintain e.g., when obvious
side effects are associated with a drug
What is the difference between randomisation and random sampling?
Randomization should not be confused with random
sampling! Random sampling refers to recruiting a sample from
the source population into the study; if this sampling is not
random then the study will be prone to selection bias.
What is the difference between blinding and allocation concealment?
Blinding should not be confused with allocation
concealment! Allocation concealment takes place before and
during participant allocation to intervention/control group,
whereas blinding occurs after participant allocation (i.e. during
study conduct – collection of outcome measurements).
BASIC DESIGN OF RCT DIAGRAM
MAIN PROBLEMS IN RCTs
What are the 3 main problems in RCTs?
- Loss to follow-up
- Non-compliance
- Contamination
Why would patients be lost to follow-up?
Side effects, moved, died, recovered, got worse,
lost interest
What is the consequences of loss-to-follow-up, non-compliance and contamination?
– major bias
– decreased power
– and loss of credibility
Why would patients be lost to poor compliance?
Side effects, iatrogenic reactions, recovered, got
worse, lost interest
Why would patients be lost to poor compliance?
Contamination= cross-over
ESPECIALLY IN CONTROL GROUPS IF UNBLINDED
How can we maximise FU and compliance?
By using:
1. two screening visits prior to enrollment
2. pre-randomization run-in period using placebo
or active drug
3. maintain blinding
RANDOMIZED CROSS-OVER DESIGN DIAGRAM
What are the advantages and disadvantages of Randomized Cross-over design?
- Advantages: each subject acts as his or her own control, and smaller
number of patients are required in comparison to parallel-group studies - Disadvantages: longer duration than parallel-group studies & difficulty for
multiple dosage arms and with in dealing with drop-outs
What are non-randomized and non-controlled trials?
- Sometimes allocation of participants in each treatment group
is not a result of randomization; in such a case the study is
said to be a non-randomized trial - Sometimes clinical trials can take place in a single
intervention group, with the lack of a control group; in such a
case the study is said to be a non-controlled trial - Both of the above approaches should be avoided, as the
likelihood of bias and confounding increases substantially
What are Quasi-experimental designs?
- A type of non-randomized design
*In quasi-experimental designs, participants are
assigned to a study condition using some nonrandom (but systematic) procedure - i.e., month of birth, every 2nd patient who comes,
etc
What are the advantages of RCT designs?
- Measures efficacy and safety of an intervention
- High internal validity: Able to control selection,
confounding and measurement biases - Prospective – Incidence study – cause-effect
What are the disadvantages of RCTs?
- They are time- and energy- intensive (Phase I - III)
- They are expensive
- They may not be feasible for all interventions or
settings - Not good for rare outcomes (as cohort studies)
- The ability to make valid inferences (internal and
external validity) depends on how well the
investigator designed, conducted, and reported
various procedures to minimize bias in the study
SUMARRY OF RCTs
- The key methodological components of an RCT are
(1) use of a control condition to which the
experimental intervention is compared; and
(2) random assignment of participants to conditions - Random assignment reduces confounding bias
- Concealment reduces selection bias
- Blinding reduces biased measurement
- Limitations: contamination, loss to FU, noncompliance
FU=Follow-Up
