Clinical Trials

Question 1

Define Superiority Trials

Answer 1

Superiority Trials test whether a new drug is better than a comparator (e.g. placebo or current best treatment)

Question 2

Define Equivalence Trials

Answer 2

Equivalence Trials test whether a new drug is the same as an existing treatment

Question 3

Define non-inferiority Trials

Answer 3

Non-inferiority Trials test whether a new treatment is no worse than an existing treatment

Question 4

Clinical equivalence trials

Answer 4

Tests whether clinical outcomes for a new drug are the same as for an existing treatment

Question 5

Bioequivalence trials

Answer 5

Tests whether PK parameters e.g. blood concentrations or receptor occupancy for a new drug are the same as for an exisitng treatment

Question 6

Compare and contrast Superiority, equivalence and non-inferiority trial designs

Answer 6

Superiority:
Most clinical trials
Treatment advance (comparison with placebo or existing best practice)

Equivalence:
Treatment change, comparison with original
(change in drug delivery or manufacture…generic drugs or biosimilars)

Non-Inferiority:
Current effective treatments, where placebo would be unethical
(new treatments may have secondary advantages e.g. better safety, acceptability, cost)

Question 7

What are factors that determine an ‘ideal clinical trial’?

Answer 7

The ideal clinical trial determines the safety and efficacy of a new drug

-Clinically meaningful (represents a meaningful advance in healthcare/patient outcomes)
-Reliable (Results can be reproducible if trial is repeated)
-Valid:
Internal: observed differences can be correctly attributed to the intervention
External: trial results can be generalised to the real-world population

Question 8

State the null and alternative hypothesis for superiority trials

Answer 8

Null hypothesis: Treatment is not better than or the same as the comparator
Alternative hypothesis: Treatment is better than comparator

Question 9

State the null and alternative hypothesis for Equivalence trials

Answer 9

Null hypothesis: Treatment is not similar to comparator
Alternative hypothesis: Treatment is similar to comparator

Question 10

State the null and alternative hypothesis for non-inferiority trials

Answer 10

Null hypothesis: Treatment is worse than comparator
Alternative hypothesis: Treatment is not worse than (is the same or better than comparator)

Question 11

What is a one-sided test?

Answer 11

Tests for the possibility of a relationship in one direction.
One-sided tests provides more power to detect an effect.
Risk of missing an effect in the other direction

Question 12

What is a two-sided test

Answer 12

Tests for the possibility of a relationship in both directions

Question 13

Define Bias

Answer 13

Systematic distortion of the results of a clinical study away from the truth

Question 14

List some causes of bias in clinical trials

Answer 14

Caused by inadequacies in design, conduct or analysis of the trial or
publication of its results

Reduces validity of study results

Question 15

Per protocol analysis

Answer 15

Determines maximum potential effectiveness of treatment

Don’t have to worry about drop outs

Question 16

Intention to treat

Answer 16

Preserves randomisation
* Minimises bias
* Deals with dropouts
* Mirrors real life
* Allows interim analysis
* Practical and pragmatic
* Might miss a real effect

Question 17

Define confounders

Answer 17

A parameter that is related to both the study treatment and the outcome, but is not caused by the treatment. Confounders can interfere with the ability of a trial to produce a true result and should be controlled for in study design by randomisation

Question 18

How can confounders be minimised?

Answer 18

Randomisation

Stratification

Minimisation

Question 19

Define randomisation

Answer 19

A process of allocating participants to study groups that gives everyone an equal chance of being allocated to any group

Question 20

Define stratification

Answer 20

Randomisation within subgroups of key confounders

Question 21

Define minimisation

Answer 21

Dynamic method of randomisation that assigns participants to treatment groups in an order that minimises overall imbalance between groups for a number of selected confounding factors

Question 22

Define Type 1 error

Answer 22

Rejecting the null hypothesis when it is true, false positive result

Designated as alpha, usually set at 0.05 (5%)

Question 23

Define Type 2 error

Answer 23

Failing to reject the null hypothesis when it is false, false negative result

Designated as beta, usually set at 20%

Question 24

How is the risk of random error reduced?

Answer 24

Reduced by large sample
and less variance

Question 25

Define power (of a study)

Answer 25

The ability of a study to find a significant result if one exists

Calculated as 100-beta (if beta is 20%, power is 80%)

Question 26

Define multiplicity

Answer 26

Performing many statistical tests on one clinical trial - increases the risk of a type 1 error/false positive result

Question 27

What is the risk of type 1 error?

Answer 27

[1-(1-alpha)n], where n is the number of tests performed and alpha is the type 1 error rate

Question 28

Define minimisation

Answer 28

Dynamic method of randomisation that assigns participants to treatment groups in an order that minimises overall imbalance between groups for a number of selected confounding factors

Question 29

Define stratification

Answer 29

Randomisation within subgroups of key confounders

Question 30

What is an interim analysis

Answer 30

Analysis conducted during the trial for ethical or economic reasons - trial may be terminated early if significant differences in efficacy or safety are identified

Question 31

Define Bonferroni correction

Answer 31

Reducing the alpha of statistical tests to reduce the risk of a false positive result - divide 0.05 by the number of tests to set the significance level for the subtests

Question 32

Define covariate

Answer 32

Baseline characteristic (e.g. age, sex) that accounts for some of the variance in an outcome measured in a clinical trial (e.g. age is associated with increased risk of mortality). May modify the effect of a new treatment (e.g. drug may work in younger but not older patients)