1.3 Clinical Trials

Question 1

Definition of 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 and efficacy and safety

Question 3

Define efficacy

Answer 3

The ability of a healthcare intervention to improve the health of a defined group under specific conditions

Question 4

Define safety

Answer 4

The ability of a healthcare intervention not to harm a defined group under specific conditions

Question 5

Efficacy vs effectiveness

Answer 5

Efficacy- measured in ideal clinical conditions, mostly used by pharmaceutical companies
Effectiveness- real world clinical experience, more significant for clinicians

Question 6

What 3 things does a clinical trial need to be? And why?

Answer 6

Reproducible
Controlled- so that the effects of the new treatment are isolated and can confirm the outcomes are down to the treatment
Fair- unbiased

Question 7

What are the stages of drug development?

Answer 7

Preclinical -> 1. Volunteer studies –> 2. Treatment studies –> 3. Clinical trials –> 4. Post marketing surveillance

Question 8

Explain the disadvantages of comparison with historical controls

Answer 8

Selection often less well defines
Less info available about potential bias or confounders
Lack of control of the other treatments provided by the hospital
Hospital care changes with time
Populations change with time

Question 9

Explain the disadvantages of non randomised clinical trials

Answer 9

Allocation bias and confounding variables
Hospital management might be different
Populations might be varying e.g. ethnicity

Question 10

Outline the steps involved in a randomised controlled trial

Answer 10

Definition of key study variables
Conduct of the trial
Comparison of the outcomes

Question 11

RCT: step 1 Define

Answer 11

Define:
The disease of interest and which patients would be eligible
Which treatments are being compared e.g. 2 drugs or vs a placebo
What outcomes are being measures
Are there any possible biases or confounders

Question 12

RCT: Step 2 Conduct of the trial

Answer 12

Identify and invite a source of eligible patients with consent
Allocate patients fairly
Follow up in identical ways
Minimise losses to follow up and maximise adherence

Question 13

RCT Step 3 Comparison of outcomes

Answer 13

Statistically significant? CLincially significant? Good design?

Question 14

Why do we need to have ore-defining outcomes?

Answer 14

It prevents data dredging and repeating analyses, it is protocol for data collection and have agreed criteria

Question 15

What is the difference between primary and secondary outcomes?

Answer 15

Primary- used in the sample size calculation and tends to be mortality. Mortality is the most common used by companies
Secondary- Eg QOL, ejection fraction

Question 16

Types of outcomes

Answer 16

Patho-physiological e.g. tumour size, thyroxine levels
Clinical e.g. death, disease, disability
Patient focused e.g. QoL, psychological well-being, social well-being, satisfaction

Question 17

Features of an ideal outcomes

Answer 17

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

Question 18

What does random allocation allow?

Answer 18

Minimal allocation bias and minimal confounding variable, works for known and unknown variables

Question 19

What is a confounder?

Answer 19

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

Question 20

What are the most common confounding variables

Answer 20

Age and sex

Question 21

What effect can knowing the treatment allocation have on the trial? How does it effect the three parties of the trial?

Answer 21

May bias the results.
Patients- behaviour effect
Clinician- non treatment effect
Investigator- measurement bias

Question 22

How can we avoid allocating bias?

Answer 22

Blinded trials

Question 23

Describe the placebo effect

Answer 23

Even if the therapy is irrelevant to the patients condition, the patients attitude to his or her illness, and indeed the illness itself, may be imoirced by a feeling that something is being done about it.

Question 24

What is a placebo, what is its function?

Answer 24

An inert substance made to appear identical to treatment which it is compared to.
The aim is to cancel out placebo effect

Question 25

What are the ethical implications of a placebo?

Answer 25

It should only be used in the absence of standard treatment Use of a placebo is a form of deception Therefore patients must be informed they may be receiving a placebo

Question 26

How does one overcome losses to follow up?

Answer 26

Make the follow up practical and minimise inconvenience Be clear and honest about the commitment required from participants Avoid coercion or inducements Maintain contact with patients

Question 27

How does one overcome non-compliance with treatments

Answer 27

Simplify the instructions Ask abut compiance Ask about effects and side effects

Question 28

What are reasons for non-compliance?

Answer 28

``` May have misunderstood instructi9ons May not like their treatment May think their treatment is not working May switch to other treatment Cant be bothered ```

Question 29

What is an explanatory trial also known as?

Answer 29

'As treated' analysis

Question 30

Describe explanatory trials:

Answer 30

Analyses only those who completed the follow up and complied with treatment and compares the physiological effects of the treatments

Question 31

What is the disadvantage of explanatory trials

Answer 31

Loses the effects on randomisation as the non compilers are likely to be systematically different to the compliers so there is selection bias and confounding

Question 32

What is a pragmatic trial also known as?

Answer 32

Intention to treat analysis

Question 33

Describe pragmatic trials

Answer 33

Analyses according to the original allocation to treatment groups regardless of compliance or follow pu and compares the likely effects of using treatment in routine clinical practice PRESERVES RANDOMISATION

Question 34

'As treated' vs 'Intention to treat'

Answer 34

As treated analyses tend tp give larger sizes of effect | Intenti0on to treat analyses tend to give snakier and fire realistic size of effect- this is the preferred option

Question 35

Declaration of Helsinki 2013

Answer 35

“The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”

Question 36

What is collective ethic?

Answer 36

All patients should have treatments that are properly tested for efficacy and safety

Question 37

What is individual ethic?

Answer 37

Beneficiance Non Maleficience Autonomy Justice

Question 38

What are the issues that should be considered for a clinical trial to be ethical?

Answer 38

Clinical equipoise- when there is reasonable uncertainty to genuine ignorance about the better treatment or intervention Scientifically robust- addresses the question Ethical recruitment Valid consent Voluntariness