Clinical Trials

Question 1

The pre-clinical phase of drug development involves what?

Answer 1

Laboratory studies
Pharmacology
Animal toxicology
Cell cultures

Question 2

Phase I of drug development involves what?

Answer 2

Volunteer studies
Pharmacodynamics 
Pharmacokinetics 
Major side-effects 
In <100 healthy volunteers

Question 3

Phase II of drug development involves what?

Answer 3

Treatment studies
Effects and dosages
Common side-effects
In <1000 patients

Question 4

Phase III of drug development involves what?

Answer 4

Clinical trials
Comparison with standard treatments
In <10000 patients

Question 5

What does phase IV of drug development involve?

Answer 5

Post-marketing surveillance
Monitoring ADRs
In the whole population

Question 6

What is an orphan drug?

Answer 6

A synthetic pharmaceutical that remains commercially unavailable, for economic reasons for e.g.

Question 7

“Scientifically proven to work” means what in terms of the benefit of taking the drug?
Is this the absolute or relative risk?

Answer 7

You are not necessarily more likely to benefit than not… BUT it is better than the other treatment.
Relative risk

Question 8

What is the definition of a clinical trial?

Answer 8

Any form of planned experiment which involves patients and is designed to elucidate the most appropriate method of treatment for future patients with a given medical condition.

Question 9

What is the purpose of performing clinical trials?

Answer 9

To provide reliable evidence of treatment efficacy and safety.

Question 10

In order to be able to give a fair comparison of effect and safety, a clinical trial needs to be….

Answer 10

Reproducible
Controlled
Fair (unbiased, no confounding)

Question 11

What are some disadvantages of non-randomised clinical trials?

Answer 11

Allocation bias
-by patient, clinician, investigator

Confounding
-known, unknown

Question 12

What are the disadvantages of comparison with historical controls?

Answer 12

For the ‘standard treatment’ group:

• selection often less well defined
• treated differently from ‘new treatment group’
• less information about potential bias/confounders
• unable to control for confounders

Question 13

Outline the three steps involved in RCT.

Answer 13

1. Definition of factors
2. Conduct of the trial
3. Comparison of outcomes

Question 14

RCT: “Definition of factors” involves defining what?

Answer 14

• The disease of interest
• The treatments to be compared
• The outcomes to be measured
• Possible bias and confounders
• The patients eligible for the trial
• The patients to be excluded from the trial

Question 15

RCT: “Conduct of the Trial” involves what steps?

Answer 15

• Identify a source of eligible patients
• Invite eligible patients in the trial
• Consent patients willing to be in the trial
• Allocate participants to the treatments fairly
• Follow-up participants in identical ways
• Minimise losses to follow-up
• Maximise compliance to treatments

Question 16

During RCT: “Comparison of Outcomes” what questions are we hoping to answer?

Answer 16

Is there an observed difference in outcome between the treatment groups?

Could the observed difference have arisen by chance i.e. is it statistically significant?

How big is the observed difference between the treatment groups i.e. is it clinically important?

Is the observed difference attributable to the treatments compared in the trial?

Question 17

Why do we set pre-defined outcomes before clinical trials?

Answer 17

Prevent data dredging & repeated analysis
Protocol for data collection
Agreed criteria for measurement and assessment of outcomes

Question 18

Name three types of outcome and give examples of each.

Answer 18

Patho-physiological
e.g. tumour size, thyroxine level, ECH changes

Clinically defined e.g. mortality, morbidity, disability

Patient-focussed e.g. QoL, psychological well-being, social well-being, satisfaction

Question 19

What do we mean by monitoring for possible effect?

Answer 19

Seeing if one group is being disadvantaged.

Question 20

What do we mean by monitoring for adverse effect?

Answer 20

Seeing if patients are being harmed.

Question 21

What is non-random allocation?

Answer 21

Allocation of [articipants to treatments by a person, historical basis, geographical location etc.

Question 22

What can non-random allocation lead to that might be detrimental to the validity of the clinical trial?

Answer 22

Allocation bias

Confounding factors

Question 23

How can we achieve minimal allocation bias?

Answer 23

Ensuring that randomisation gives each participant an equal chance of being allocated to each pf the treatments in the trial.

Question 24

What is the difference between single, double and triple blind?

Answer 24

Single- one (usually patient) does not know the treatment allocation
Double- two of patient, clinician, assessor does not know the treatment allocation
Triple- all do not know the allocation including analysis

Question 25

What examples can you give where blinding may be difficult?

Answer 25

Surgical procedures
Psychotherapy vs. antidepressants
Lifestyle interventions
Prevention programmes

Question 26

Define what is meant by the placebo effect.

Answer 26

Even if the therapy is irrelevant to the patient’s condition, the patient’s attitude to their illness and indeed the illness itself may be improved by feeling that something is being done about it.

Question 27

What is a placebo?

Answer 27

An inert substance made to appear identical in every way to the active formulation with which it is to be compared.

Question 28

What are the two types of losses to follow up for clinical trials?

Answer 28

Appropriate- their clinical condition necessitates their removal

Unfortunate- they choose to remove themselves from the trial

Question 29

How can we maximise compliance with treatments?

Answer 29

Simplify instructions
Ask about compliance
Ask about effects/side-effects
Monitor compliance

Question 30

What is the difference between “explanatory” and “pragmatic” trials?

Answer 30

Explanatory trials ignore those who didn’t take the treatment
“As-treated”

Pragmatic trials analyses all regardless of whether they completed follow-up or treatment
“Intention-to-treat”

Question 31

Should clinical trials be analysed on an explanatory or pragmatic basis?
Why?

Answer 31

Pragmatic (intention-to-treat)

Because they tend to give smaller and more realistic sizes of effect and preserves effects of randomisation