Week 11- Interventional Studies

Question 1

OVERALL DIAGRAM

Answer 1

Question 2

TIMELINE DIAGRAM

Answer 2

Question 3

What are experimental (intervention) studies?

Answer 3

– 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

Question 4

Why is experimental studies regarded as the most scientifically vigorous study design?

Answer 4

• Random assignment reduces confounding bias
• Concealment reduces selection bias
• Blinding reduces biased measurement (information bias)

Question 5

What are prophylactic trials?

Answer 5

Evaluate efficacy of intervention
designed to prevent disease, e.g., vaccine, vitamin
supplement, patient education

Question 6

What are treatment trials?

Answer 6

Evaluate efficacy of curative drug or
intervention or a drug designed to manage signs and
symptoms of a disease (e.g., arthritis, hypertension)

Question 7

What are RCT trials?

Answer 7

Individuals, tightly controlled, narrowly
focused, highly select groups, short or long duration

Question 8

What are community/ cluster trials?

Answer 8

Cities/regions/schools/hospitals, less rigidly controlled,
long duration, usually primary prevention

Question 9

How many clinical trial phases are there?

Answer 9

4

Question 10

What does phase 1 include?

Answer 10

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)

Question 11

What does phase 2 include?

Answer 11

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)

Question 12

What does phase 3 include?

Answer 12

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

Question 13

What does phase 4 include?

Answer 13

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

Question 14

What is a randomised controlled trial (RCT)?

Answer 14

• 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

Question 15

Why is randomisation important?

Answer 15

1. 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
2. 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

Question 16

What does Allocation Concealment mean?

Answer 16

Allocation concealment means that the person who
generates the random assignment remains blind to what
condition the person will enter

Question 17

Why is allocation concealment important?

Answer 17

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%

Question 18

What is blinding?

Answer 18

• 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

Question 19

What is double-blinding?

Answer 19

• 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

Question 20

What are the 2 types of groups in RCTs?

Answer 20

1. Intervention group= receives treatment of interest
2. Control group= receives placebo/another treatment

Question 21

What is a placebo?

Answer 21

A Substances (usually a pill) identical to intervention substance, but LACKS THE ACTIVE INGREDIENTS (chemically inert)

Question 22

What is the placebo effect?

Answer 22

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

Question 23

What is the goal of Placebo-controlled trials?

Answer 23

Allows for the study of effectiveness of intervention treatment BEYOND PLACEBO EFFECTS

Question 24

What is masking of placebo?

Answer 24

The same appearance, size, colour, taste (or even side effects) for active and placebo drug to reduce bias

Question 25

What are double blind trials?

Answer 25

-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

Question 26

What else can the control group be except for placebo group?

Answer 26

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)

Question 27

What is partial blinding?

Answer 27

* 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

Question 28

What are unblinded trials?

Answer 28

* 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.

Question 29

Why is blinding important?

Answer 29

* 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

Question 30

What is the difference between randomisation and random sampling?

Answer 30

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.

Question 31

What is the difference between blinding and allocation concealment?

Answer 31

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).

Question 32

BASIC DESIGN OF RCT DIAGRAM

Answer 32

Question 33

MAIN PROBLEMS IN RCTs

Answer 33

Question 34

What are the 3 main problems in RCTs?

Answer 34

1. Loss to follow-up 2. Non-compliance 3. Contamination

Question 35

Why would patients be lost to follow-up?

Answer 35

Side effects, moved, died, recovered, got worse, lost interest

Question 36

What is the consequences of loss-to-follow-up, non-compliance and contamination?

Answer 36

– major bias – decreased power – and loss of credibility

Question 37

Why would patients be lost to poor compliance?

Answer 37

Side effects, iatrogenic reactions, recovered, got worse, lost interest

Question 38

Why would patients be lost to poor compliance?

Answer 38

Contamination= cross-over ESPECIALLY IN CONTROL GROUPS IF UNBLINDED

Question 39

How can we maximise FU and compliance?

Answer 39

By using: 1. two screening visits prior to enrollment 2. pre-randomization run-in period using placebo or active drug 3. maintain blinding

Question 40

RANDOMIZED CROSS-OVER DESIGN DIAGRAM

Answer 40

Question 41

What are the advantages and disadvantages of Randomized Cross-over design?

Answer 41

* 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

Question 42

What are non-randomized and non-controlled trials?

Answer 42

* 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

Question 43

What are Quasi-experimental designs?

Answer 43

* 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

Question 44

What are the advantages of RCT designs?

Answer 44

* Measures efficacy and safety of an intervention * High internal validity: Able to control selection, confounding and measurement biases * Prospective – Incidence study – cause-effect

Question 45

What are the disadvantages of RCTs?

Answer 45

* 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

Question 46

SUMARRY OF RCTs

Answer 46

* 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