Clinical Trial Designs and Evaluation (5&6)

Question 1

Design Issues

Answer 1

1. Primary Question
2. Study population
3. Randomization
4. Blinding
5. Control Groups

Question 2

Every clinical trial has to have a ____ ____. This as well as secondary questions should be selected carefully an clearly defined and stated.

Answer 2

Primary Question (can be put into a statement)

Question 3

Examples of Primary and Secondary questions

Answer 3

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.

Question 4

Study population

Answer 4

should be defined in advance, stating unambiguous inclusion and exclusion (eligibility) criteria.

Question 5

The study population is the _____ of the population with the condition or characteristics of interest defined by the eligibility criteria.

Answer 5

subset

Question 6

The trial participants are selected from

Answer 6

the study population.

Question 7

Eligibility for study population

Answer 7

relate to participant safety and anticipated effect of the intervention.

Question 8

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.

Answer 8

detecting the hypothesized effects of the intervention.

Question 9

Randomized controlled trials (RCTs)

Answer 9

are comparative studies with an intervention group and a control group.

Question 10

The randomization procedure ______ assigns the participant to one group or the other.

Answer 10

randomly

Question 11

Random assignment to treatment is only ethical when there is genuine ____ _____ _______ ______ ___ ____ ____ __ ______

Answer 11

uncertainty on the part of the relevant expert community about which therapy is most effective for a given condition (“clinical equipoise”).

Question 12

Clinical equipois

Answer 12

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

Question 13

Advantages of Randomization:

Answer 13

1. Removal of bias
2. Comparable groups
3. Statistical validity

Question 14

Randomization ____ potential bias in allocating participants to groups

Answer 14

removes

Question 15

Selection bias is

Answer 15

due to bias

Question 16

Bias can easily occur in a ___ ______ ______ because the investigator or the participant may influence the choice of intervention.

Answer 16

non-randomized study

Question 17

This influence of bias can be _____ or ________and can be due to numerous factors, including the prognosis of the participant.

Answer 17

conscious or subconscious

Question 18

Bias

Answer 18

Can easily invalidate the trial results.

Question 19

Comparable groups

Groups that are the same in both known and unknown characteristics

Answer 19

Randomization results in groups that are the same for important characteristics (known and unknown).

Question 20

In comparable groups we can say the groups being compared tend to be

Answer 20

“evenly balanced.”

Question 21

An advantage of randomization results in statistical validity

Answer 21

The validity of statistical tests of significance is guaranteed.

Question 22

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.

Answer 22

statistical models

Question 23

Non randomized clinical trials

Answer 23

Establishing the validity of these assumptions may be difficult.

Question 24

Non-Randomized Control Studies

Answer 24

Participants are allocated to one of two (or more) groups, but the allocation is not a random process.

Question 25

Non-Randomized Control Studies Examples

Answer 25

1. Surgery vs Medical clinical | 2. Patient offered two treatments and chooses

Question 26

The major weakness of non-randomized control studies is the potential that the

Answer 26

intervention group and control group are not strictly comparable (bias). (We lost comparability and Statistical validity as as well as bias)

Question 27

In non randomized control studies, comparisons between groups ___ __ ____, using statistical techniques to adjust for observed baseline imbalances. __ ______ ______ ______

Answer 27

Can be made Regardless, bias is difficult to overcome.

Question 28

Randomization in review

Answer 28

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.

Question 29

Bias can be caused by

Answer 29

conscious factors, subconscious factors, or both.

Question 30

One solution to the problem of bias is to

Answer 30

keep the participants and the investigators blinded, or masked, to the identity of the assigned intervention.

Question 31

Single-Blind:

Answer 31

Only the participants are unaware of the treatment (or placebo) they are receiving.

Question 32

Double-Blind:

Answer 32

Neither the participants nor the investigators know the identity of the intervention assigned.

Question 33

Ideally, trials should be _____-______ in order to limit potential problems of bias during data collection and assessment.

Answer 33

double-blinded

Question 34

Numerous steps must be taken to maintain the blind, | like:

Answer 34

e.g., identical tablet appearance and taste, coding of drugs bottles, identical treatment administration.

Question 35

For some trials, e.g., many surgery trials, blinding is __ ______.

Answer 35

not feasible.

Question 36

Sound scientific clinical investigation almost always demands that a _____ _____ be used against which the new intervention can be compared.

Answer 36

control group

Question 37

Randomization is the preferred way of

Answer 37

assigning participants to control and intervention groups.

Question 38

Most trials use the so-called

Answer 38

parallel design or concurrent control

Question 39

Parallel design

Answer 39

the intervention and control groups are followed simultaneously from the time of allocation to one or the other (concurrent control).

Question 40

Historical control studies

Answer 40

these compare a group of participants on a new intervention with a previous group of participants on standard or control therapy.

Question 41

Concurrent (Parallel) Control Studies

Answer 41

When both the control and the intervention are doing it at the same time

Question 42

Types of Concurrent (Parallel) Control Studies

Answer 42

1. Cross-over trial (each person is part of both the intervention and control) 2. Withdrawal study, in which everyone is first on the intervention then half and half

Question 43

(Parallel Control Study) Participants in the control group may be on

Answer 43

placebo, no treatment, usual or standard-of-care, or a specified treatment.

Question 44

Principal difference between placebo and no treatment is that a no-treatment trial is

Answer 44

not blinded. | if there is no placebo they know they are receiving nothing thus not blinded

Question 45

Cross-over trial (type of parallel control study)

Answer 45

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.

Question 46

Withdrawal study (type of parallel control study) This one is randomized

Answer 46

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.

Question 47

A placebo is an

Answer 47

inactive substance or intervention, such as an inactive tablet or sham surgery, that resembles the comparable active substance or intervention.

Question 48

A new intervention is added to ____ or _______ and compared against that care plus placebo.

Answer 48

usual care or standard-of-care and compared against that care PLUS PLACEBO

Question 49

A placebo ___ ___ ____ ______ if an existing therapy has been proven beneficial (standard-of-care).

Answer 49

may not be considered ethical

Question 50

Placebo is not always feasible

Answer 50

especially for some surgery and oncology trials

Question 51

Placebo effect

Answer 51

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.

Question 52

Failed Blinding with Placebo

Answer 52

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

Question 53

Cross-Over Designs

Answer 53

each participant receives either intervention or control (A or B) in the first period and the alternative in the succeeding period.

Question 54

(In Cross over designs) | Each participant serves as his or her own .

Answer 54

control

Question 55

(In Cross over designs) | The order in which A and B are given to each participant is ______.

Answer 55

randomized Thus, approximately half of the participants receive the intervention in the sequence AB and the other half in the sequence BA.

Question 56

Fairly strict assumption must be made about cross over designs:

Answer 56

effects of intervention during first period must not carry over into second period. Often can’t be made.

Question 57

(In Cross over designs) | May require ___________ between periods.

Answer 57

“wash-out"

Question 58

Withdrawal Studies

Answer 58

Participants on a particular treatment (e.g., for a chronic disease) are taken off therapy or have the dosage reduced.

Question 59

(In withdrawal studies) Objective of these studies is to _____ _______ __ _________ __ _____ _______

Answer 59

assess response to discontinuation or dose reduction.

Question 60

(In withdrawal studies) This design may be validly used to evaluate the _______ of benefit of an intervention already known to be useful.

Answer 60

duration

Question 61

In historical control studies

Answer 61

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).

Question 62

Historical controls are, by definition, ___________.

Answer 62

nonrandomized

Question 63

The argument for using a historical control design is that

Answer 63

all new participants can receive the new intervention. Many clinicians believe that all participants should have the possibility of receiving a new therapy.

Question 64

Historical control studies are particularly vulnerable to _____.

Answer 64

bias

Question 65

An improvement in outcome for a given disease may be attributed to a new intervention when, in fact, the improvement may stem from

Answer 65

a change in the patient population or patient management.

Question 66

HCTs (79%) and RCTs (20%)

Answer 66

more bias in finding better results of with historical control studies

Question 67

Shown to be harmful through the use of RCTs

Answer 67

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

Question 68

Shown to be beneficial through the use of RCTs

Answer 68

β blockers in heart failure Digoxin after myocardial infarction

Question 69

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.

Answer 69

primary question study population