Epidemiology Lecture 1 -- Randomized Control Trials

Question 1

Define RCTs

Answer 1

The gold standard study design from which evidence on efficacy is assessed. As close to a scientific experiment as is possible in study of humans

Question 2

3 reasons to do an RCT

Answer 2

1) To test an intervention in patients
2) Field or prevention studies in healthy patients (ie. vaccines)
3) Community trials where groups of people are studied

Question 3

3 disadvantages of RCTs

Answer 3

1) Costly and time consuming
2) Infeasible in many instances (ethics)
3) Many questions of medical interest cannot be addressed (i.e. cannot withhold a therapy that is proven to be active)

Question 4

How is randomization carried out and why

Answer 4

Use a chance mechanism (computer generated now) so that neither patient nor physician know in advance which therapy will be assigned

Question 5

2 goals of randomization

Answer 5

Ensures that every person has the same and independent chance as any other person in receiving either intervention

Ensures than the intervention groups are similar on average at baseline

Question 6

What is randomization highly dependent on?

Answer 6

Size of the study

Question 7

What is the purpose of stratified randomization?

Answer 7

Ensure equal numbers of two groups when an important known and measurable risk factor is taken into account (i.e. males have more risk for CVD than women, so make sure study isnt skewed towards men by ensuring equal numbers of men and women in both groups)

Question 8

What limits stratified randomization

Answer 8

Small sample size

Large number of strata

Question 9

2 advantages of randomization

Answer 9

Eliminate conscious bias (physician and patient self selection)

Balance unknown biases among treatment groups (i.e. non-measurable/non-stratifiable factors or unknown factors affecting outcome)

Question 10

2 disadvantages of randomization

Answer 10

Patient or physician may not care to participate in experiment involving a chance mechanism to decide treatment

May influence patient-physician relationship (i.e. if pressure to recruit)

Question 11

Define the “control” aspect of RCTs

Answer 11

Manipulation and measurement of exposure (treatment)

Question 12

5 examples of control in RCTs

Answer 12

Who gets what
The exact timing of when drug is administered
Control over when follow-up measurements are made
Same data collection from both groups
Same outcome assessment using validated tools

Question 13

Purpose of control in RCTs

Answer 13

Provides the best means of avoiding bias and confounding, and quantifying the uncertainty in a statistical procedure

Question 14

Define blinding

Answer 14

Process of hiding treatment allocation to people involved in the study in an effort to avoid bias (= impossible to distinguish between interventions)

Question 15

4 levels of blinding

Answer 15

Treatment allocation
Patient
Investigator
Measurement of outcome

Question 16

Levels of blinding most often involved in double blinding

Answer 16

Patient

Investigator

Question 17

Levels of blinding most often involved in triple blinding

Answer 17

Patient
Investigator
Measurement of outcome

Question 18

2 ways that blinding can be impractical

Answer 18

Side effects may be too obvious to blind

Increases pill burden

Question 19

Define open-label

Answer 19

No blinding (i.e. if the drug is clearly unblindable)

Question 20

Problem with using placebos

Answer 20

Increases pill burden when using active comparator (i.e. not testing how drug will actually be administered = issue for compliance)

Question 21

Define equipoise

Answer 21

A state of genuine uncertainty about the benefits or harms that may result from each of two or more regimens. A state of equipoise = an indication for an RCT since there are no ethical concerns about one regimen being better for a particular patient

Question 22

Define the reference population

Answer 22

Everyone who can benefit from the drug

Question 23

Define the experimental population

Answer 23

Everyone you can access and recruit for the experiment

Question 24

Define the study population

Answer 24

People who fit the criteria for the study

Question 25

Define non-participants

Answer 25

People who do not fit the criteria of the study (i.e. have a comorbid disease) NOTE: must be documented

Question 26

When must compliance be ensured?

Answer 26

At recruitment stage and during entire study

Question 27

How can compliance be ensured during the study?

Answer 27

Make it easy for the patient to comply, such as providing transportation, easily accessible prescription, professionalism/courtesy, provision of medical info during course of the trial, etc.

Question 28

Some examples of how to measure compliance

Answer 28

Pill counts Biochemical markers Self-report

Question 29

Define the Hawthorne effect

Answer 29

Participation in the trial may affect the outcomes since the patient may be so well-cared for that the effect is disproportionately positive

Question 30

Who conducts interim analyses?

Answer 30

Data and Safety Monitoring Board (DSMB), who are blinded to treatment allocation

Question 31

What is a criterion for early termination of a study?

Answer 31

A strong statistical difference between groups or no difference at all

Question 32

4 aspects of a statistical analysis plan

Answer 32

Outline what is the primary endpoint to be studied What tests will be used to define the endpoint How missing data/visits will be handled What secondary analyses will be done

Question 33

4 statistical issues

Answer 33

1) Sample-size and power 2) Analyses using intention-to-treat (ITT) vs. per protocol (evaluable; PP) populations 3) Interim analyses monitoring (safety and/or efficacy; stopping rules) 4) Losses to follow-up and missing data

Question 34

Define Type I error (or alpha)

Answer 34

The study results show an association, but there is none in reality

Question 35

Define Type II error (beta)

Answer 35

Study shows no effect, but there is an association in reality

Question 36

Define power

Answer 36

When there is an association in reality and the study shows it

Question 37

Calculate power

Answer 37

1 - beta

Question 38

Arbitrary % for sufficient power and what it means

Answer 38

80% = we accept a 20% chance of missing a true effect

Question 39

Relationship between sample size and power

Answer 39

Larger sample size = greater power

Question 40

Relationship between loss to follow up and power

Answer 40

Loss-to-follow-up must be taken into account in study design. May need to inflate sample size, for example by 2, if you expect a 50% dropout rate

Question 41

Define efficacy

Answer 41

Measure of how active the drug is when taken according to exact protocol = maximum estimate of a drug's potential activity

Question 42

What population is included in measuring efficacy?

Answer 42

Includes only those who have adhered to the protocol (on treatment or pro-protocol analysis)

Question 43

Define effectiveness

Answer 43

Measure of how the therapy will function in real life

Question 44

What population is included in measuring effectiveness?

Answer 44

Everyone as they were originally randomized (thus preserves randomization)

Question 45

2 types of outcomes

Answer 45

1) A proportion with disease or achieving a pre-determined target level of a surrogate marker for disease (i.e. reduced cholesterol level, HIV viral load) 2) Time-to-event or survival (i.e. for screening)

Question 46

Define number needed to treat (NNT)

Answer 46

The number of patients who need to be treated in order to prevent one additional bad outcome

Question 47

Calculate NNT

Answer 47

The inverse of the absolute risk reduction (ARR) ``` NNT = 1/ARR ARR = |CER - EER| ```

Question 48

What do CER and EER stand for?

Answer 48

``` CER = control group event rate EER = experimental group event rate ```

Question 49

What is a generally good NNT?

Answer 49

<10

Question 50

What is a perfect NNT?

Answer 50

1 (everyone benefits from the treatment without any adverse effects; everyone gets better with treatment and no one gets better with control)

Question 51

What is an example of an event rate?

Answer 51

Mortality rate (an adverse event)

Question 52

Define phase 1 trials

Answer 52

First trial using human subjects (after in vitro and animal studies)

Question 53

Study population of phase 1 trials

Answer 53

Generally done in healthy volunteers

Question 54

Purpose of Phase 1 trials

Answer 54

Determine pharmacokinetics and pharmacological effects (basically to determine is the drug is safe)

Question 55

Drug used in phase 1 trials

Answer 55

Often use preparation of medication that is not in final marketed form

Question 56

Population of phase 2 trials

Answer 56

In a limited number of subject having the disease of interest

Question 57

Purpose of phase 2 trials

Answer 57

To determine drug effectiveness and side effects (look for optimal dose to use in later trials) Look at short term effects

Question 58

Population of phase 3 trials

Answer 58

Larger number/spectrum of subjects with the disease of interest; generally ideal (i.e. study population as defined earlier)

Question 59

When are phase 3 trials carried out?

Answer 59

After phase 2 and 1 have demonstrated effectiveness and short-term safety

Question 60

Which phase is highly regulated by the FDA and HPB? Why?

Answer 60

Phase 3 since the drug is in marketed form. This type of trial is necessary for a drug or intervention to be licensed

Question 61

2 ways to carry out a phase 3 trial

Answer 61

Compare new drug to no therapy (placebo) | Compare new drug with existing standard of care

Question 62

Traditional question of a superiority trial

Answer 62

Is the new treatment better than no (or the old) treatment?

Question 63

Goal of a non-inferiority trial

Answer 63

Show that new treatment is not worse than the standard treatment (active control) by more than a pre-specified amount (the "non-inferiority" margin), thus establishing an acceptable efficacy profile for the new treatment

Question 64

Caveat of non-inferiority trials

Answer 64

For validity, non-inferiority threshold must be set BEFORE trial is initiated

Question 65

When is phase 4 carried out?

Answer 65

Post-marketing

Question 66

Purpose of phase 4

Answer 66

To obtain additional information than what was studied in phase 3 (i.e. different dosages, durations, diseases and subpopulations)