Sept 27

Question 1

What are reasons to conduct an RCT?

Answer 1

• to evaluate a new intervention before it is given regulatory approval
• to gain regulatory approval for a new intervention
• to evaluate interventions that are controversial or that are widely used without adequate evidence

Question 2

Describe a phase 1 trial

Answer 2

• recruit small amount of healthy volunteers
• all of them get new drug
• follow them to see toxic/pharmacological effects
• not an RCT (not randomized)

Question 3

Describe a phase 2 trial

Answer 3

• recruit about 100-200 people with the disease of interest
• all get the drug
• purpose is to assess safety and efficacy
• not an RCT

Question 4

Describe a phase 3 trial

Answer 4

• conduct to get regulatory approval for new drugs

- RCT

Question 5

Describe a phase 4 trial

Answer 5

• continuation of follow up of RCT subjects past the official end of the RCT
• post market surveillance
• look for side effects
• detect things that you don’t see in limited time you have people enrolled in trial

Question 6

Evidence for the efficacy of a medication, and regulatory approval, should ideally be based on…

Answer 6

-placebo-controlled AND new versus standard of care intervention studies

Question 7

When are groups compared in RCT?

Answer 7

• compare groups at end of follow up
• comparisons may also be done at pre-defined points during follow up
• interim analyses can also be done (after 6 months we are going to see if one arms is doing a lot better than the other- it may be unethical to continue if this is the case)

Question 8

Single centre studies

Answer 8

-patients recruited from same clinic or hospital

Question 9

Multi centre studies

Answer 9

• patients are recruited from more than one clinic or hospital
• often necessary to recruit enough participants to meet sample size requirements

Question 10

What is stratified randomization?

Answer 10

-divide (stratify) the study population by age and sex and then randomize within each grouping

Question 11

Describe the difference between blind, double blind, and triple blind studies?

Answer 11

• blind: participant does not know whether they are receiving the treatment or placebo
• double blind: blinding of data collectors and participants, done to prevent knowledge of treatment from influencing how data are collected or analyzed
• triple blind: blinding physicians and hospital staff who treat study subjects

Question 12

What are some difficulties with blinding?

Answer 12

• blinding of patients and physicians is not always possible when there are obvious differences between interventions (eg. surgery vs collagen injection to treat female stress urinary incontinence)
• try to blind data assessors

Question 13

Does inability to blind preclude the use of RCT?

Answer 13

• no
• look for potential problems: data collection is more rigorous for patients in one group versus another, healthier patients disproportionately receive one intervention versus another (eg better/more careful treatment)

Question 14

What is a crossover trial?

Answer 14

• everyone in study receives both treatments
• randomize patients to receive treatment A or B then after a period of time switch them to receive the other intervention
• advantages: people serve as their own controls so nice idea of counterfactual, can use smaller sample size (because you use same person twice)

Question 15

What are cautions of a planned crossover trial?

Answer 15

• washout period: time between discontinuance of first intervention and start of second intervention must be long enough to eliminate any carry over effects from first intervention
• ordering effect: patients may react differently to the first intervention because of the psychological effect of being studied

Question 16

What situations can we not use a crossover trial?

Answer 16

• surgical interventions (can’t go back and reverse surgery typically)
• if disease is cured after treatment, can’t go back and give person disease again

Question 17

What is a factorial design?

Answer 17

• economical/efficient way of using same pop to test 2 different therapies
• drugs must have different outcomes and independent modes of action
• otherwise, interactions of drugs would prevent the independent study of the effects of each drug

Question 18

What are unintended crossovers?

Answer 18

• some subjects receive the intervention to which they were not randomized
• ex: trial of surgery vs collagen for urinary incontinence, could have patients who were randomized to collagen condition but later were recommended by doctor, etc. and get the surgery
• can dilute the effects of clinical study

Question 19

What do you do with unintended crossovers?

Answer 19

• to preserve randomization, analyze patients according to the group to which they were originally randomized (intention to treat analysis)
• analyze patients according to treatment they actually received (as treated analysis)
• can sometimes do both- if we see results are similar then we are relieved and say even though there were some unintended crossovers, they didn’t impact much

Question 20

What is non compliance?

Answer 20

• participants can refuse treatment, not do what they are asked, accidental crossover, drop out of study
• expected difference we see between groups begin to seem more alike than they really are

Question 21

How can we address noncompliance?

Answer 21

• ask patients to bring back pill bottle (count pills)
• urine or other tests
• run in phase (week where we try people on intervention and see how they adhere to the regimen)- could introduce some selection bias that we are only getting the most motivated people in our study

Question 22

What are RCTs trying to assess? Is internal or external validity more important in RCT?

Answer 22

• whether an intervention can work
• investigators are therefore concerned with internal validity
• to minimize drop outs/drug interactions participants often don’t have comorbid disorders (or have few)
• participants may also be chosen if they are good compliers
• this means that these participants may not be the most representative of the general population
• may not be externally valid

Question 23

Is it ethical to withhold a new intervention from patients (randomization means that some patients will not get the new intervention)?

Answer 23

-yes if the medical community is generally uncertain about whether the new intervention is better than the standard intervention (clinical equipoise)

Question 24

Why is it difficult to ensure clinical equipoise?

Answer 24

• don’t know who experts are that we should be asking

- how do we quantify how unsure these experts need to be

Question 25

Why are phase 4 studies important?

Answer 25

• RCT length of follow up is often short (12-24 weeks) due to high cost of recruitment and follow up
• may be inadequate to study long term outcomes for chronic conditions and rare side effects

Question 26

Both observational studies and RCTs compare an exposed versus non exposed group. What is the difference between the two study designs?

Answer 26

• RCTs randomize half to active group and half to placebo group
• observational studies simply ask what their exposure status was/is then follow them forward

Question 27

When would you NOT use an RCT?

Answer 27

• when you can’t randomize exposure because it is unethical (eg comparing smokers to non smokers)
• when the outcome will take a long time to develop (RCTs have relatively short follow-ups- expensive to conduct and are designed for regulatory approval)