S1: clinical trials

Question 1

What is a clinical trial?

Answer 1

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 2

What is the purpose of a clinical trial?

Answer 2

To provide reliable evidence of treatment efficacy and safety
Efficacy = the ability of a health care intervention to improve the health of a defined group under specific conditions
Safety = the ability of a health care intervention not to harm a defined group under specific conditions

Question 3

Why do you need pre-defining outcomes in clinical trials?

Answer 3

Prevent ‘data dredging’ & ‘repeated analyses’
Have a clear protocol for data collection
Agreed criteria for measurement and assessment of outcomes

Question 4

Describe primary and secondary outcomes

Answer 4

Primary – preferably only one, used in the sample size calculation
Secondary – other outcomes of interest, often includes occurrence of side-effects

Question 5

What are the different types of outcomes?

Answer 5

Patho-physiological eg. tumour size, thyroxine level
Clinically defined eg. death, disease, disability
Patient-focused eg. quality of life, satisfaction

Question 6

What are the features of an ideal outcome?

Answer 6

Appropriate and relevant 
Valid and attributable 
Sensitive and specific 
Reliable and robust 
Simple and sustainable 
Cheap and timely

Question 7

Describe the disadvantages of non-randomised clinical trials

Answer 7

Allocation bias – by patient, clinician or investigator

Confounding – known and unknown

Question 8

Describe the disadvantages of historical controls

Answer 8

For the ‘standard treatment’ group:

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

Question 9

Describe the advantages of blinding

Answer 9

Minimal allocation bias – each participant has an equal chance of being allocated to each of the treatments in the trial
Minimal confounding – randomisation leads to treatment groups that are likely to be similar in size and characteristics by chance

Question 10

How is randomisation achieved?

Answer 10

3rd party, computer generated random allocation, accessed by phone/internet

Question 11

Describe the advantages of blinding

Answer 11

Removes allocation bias – by ensuring that randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial

Question 12

Define confounder

Answer 12

A factor associated with the exposure and is independently a risk factor for the disease

Question 13

What is a placebo?

Answer 13

An inert substance made to appear identical in every way to the active formulation with which it is to be compared
Aim of the placebo = cancel out any ‘placebo effect’ that may exist in the active treatment

Question 14

Explain how to reduce losses to follow-up

Answer 14

Make the follow-up practical and minimise inconvenience
Be honest about the commitment required from participants
Avoid coercion or inducements, but can recompense participants for their time/trouble
Maintain contact with participants

Question 15

Explain how to reduce non-adherence with treatments

Answer 15

Simplify instructions 
Ask about adherence 
Ask about effects and side-effects 
Monitor adherence
Understand it is never possible to achieve 100% adherence

Question 16

Describe an explanatory trial

Answer 16

‘as-treated’ analysis
Analyses only those who completed follow-up and adhered to treatments
Compares the physiological effects of the treatments
BUT loses effects of randomisation
-non-adherers are likely to be systematically different from those adhering to treatment -> selection bias and confounding

Question 17

Describe a pragmatic trial

Answer 17

‘intention-to-treat’ analysis
Analyses according to the original allocation to treatment groups (regardless of whether they completed follow-up/adhered to treatment)
Compares the likely effects of using the treatments in routine clinical practice
ALSO preserves effects of randomisation -> minimal selection bias & confounding

Question 18

Compare as-treated vs intention-to-treat analyses

Answer 18

As-treated analyses tend to give larger sizes of effect
Intention-to-treat analyses tend to give smaller and more realistic sizes of effect
Clinical trials should normally be analysed on an intention-to-treat basis

Question 19

Describe the steps involved in an RCT

Answer 19

1) Set-up – disease of interest, treatments to be compared, patients eligible for trial, patients excluded, outcomes to be measured, possible bias and confounders
2) Conduct of the trial – consent, follow-up, minimise losses to follow-up, maximise adherence with treatments
3) Analysis – comparison of outcomes (statistical significance, clinically important)