Session 1: 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 efficacy and safety.

Question 3

Define efficacy.

Answer 3

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

Question 4

Define safety

Answer 4

The ability of a health care intervention not to harm a defined group under specific conditions.

Question 5

In order to be able to give a fair comparison of effect and safety, what does a clinical trial need to be?

Answer 5

Reproducible

Controlled (comparison of interventions)

Fair (unbiased)

Question 6

What are clinical trial vulnerable to?

Answer 6

Random variation (chance)

Question 7

How is chance reduced?

Answer 7

By increasing sample size

Question 8

What is the difference between efficacy and effectiveness?

Answer 8

Efficacy = ideal clinical conditions (sterile)

Effectiveness = real world clinical experience (reality)

Question 9

Give the different stages in drug development.

Answer 9

Pre-clinical phase with animals

Phase 1 with volunteers

Phase 2 is a treatment study with patients (effects and dosages as well as side effects)

Phase 3 is the clinical trial with patients (comparison with standard treatments)

Phase 4 is to whole population

Question 10

Explain the disadvantages of non-randomised clinical trials.

Answer 10

Allocation bias by patient, clinician or investigators

Confounding factors

Question 11

Explain the disadvantages of comparison with historical controls.

Answer 11

Selection is often less well defined and less rigorous

Treated differently from new treatment group

Less information about confounders and potential bias

Unable to control for confounders

Question 12

Explain the steps in a RCT conducting the trial.

Answer 12

Eligible patients

Invite patients

Consent

Allocate treatment fairly (no bias, no confounding)

Follow-up (also minimise losses)

Maximise adherence to treatments

Question 13

Reasons for Pre-defining outcomes

Answer 13

Need to define what, when and how outcomes are to be measured before start of the clinical trial.

This is to prevent data dredging and repeated analyses.

Question 14

What are primary outcomes?

Answer 14

Preferably only one primary outcome of your desired effect.

This is used in the sample size calculation.

E.g. mortality

Question 15

What are secondary outcomes?

Answer 15

Other outcomes of interest that may appear in the clinical trial.

They often include occurrence of side-effects.

Question 16

Give examples of types of outcomes.

Answer 16

Patho-physiological (tumour, thyroxine levels, ECG changes)

Clinical defined (death, disease, disability)

Patient-focused (quality of life, psychological well-being, social well-being, satisfaction)

Question 17

Give examples of an ideal outcome.

Answer 17

Appropriate and relevant

Valid and attributable

Sensitive + specific

Reliable and robust

Simple and sustainable

Cheap and timely

Question 18

Why is the timing of measurement important?

Answer 18

Using a baseline in order to monitor inadvertent differences in groups.

Monitor the possible effects as well as monitoring for adverse effects.

Final measurements

Question 19

What are the issues with non-random allocation?

Answer 19

Selection bias

Confounding factors

Question 20

What are the advantages of random allocation?

Answer 20

Minimal allocation bias

Minimal confounding factors

Question 21

Issues with knowing the treatment allocation.

Answer 21

May bias the results of the clinical trial by:

Behaviour effect (patient may alter their behaviour)

Non-treatment effect (clinician might alter their interest in the patient depending on treatment of the patient)

Measurement bias (investigators)

Question 22

Give an example of minimising allocation bias.

Answer 22

Blinding/masking

Question 23

Give examples of blinding.

Answer 23

Single blind (patient doesn’t know treatment allocation)

Double blind (patient + clinician/assessor don’t know treatment allocation)

Triple blind (usually synonymous with double blind)

Question 24

Examples where blinding is difficult.

Answer 24

Surgical procedures

Psychotherapy

Alternative medicine

Lifestyle interventions

Prevention programmes

Question 25

Advantages of blinding

Answer 25

Reducing selection bias Reducing recall or reporting bias Reducing observer bias

Question 26

Explain the placebo effect

Answer 26

Even if therapy is irrelevant to the patient's condition, the patient's attitude to his or her illness and indeed the illness itself, may be improved by **a 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 compared to.

Question 28

What is the aim of a placebo?

Answer 28

To cancel out any placebo effect that may exist in the active treatment.

Question 29

Ethical implications of placebo.

Answer 29

A placebo **should only** be used when no standard treatment is available. Use of a placebo is a form of **deception**. Important to inform the participants that they may receive a placebo.

Question 30

Give different losses to follow-up.

Answer 30

**Appropriate** loss of follow up (clinical condition may necessitate removal from trial) **Unfortunate** loss of follow up (patient may choose to withdraw)

Question 31

How to minimise losses to follow up.

Answer 31

Make follow-up **practical and convenient** Be **honest about commitment** required Avoid coercion or inducements **Maintain contact**

Question 32

Give examples of non-compliance

Answer 32

Misunderstanding of instructions Not like treatment Treatment not working Prefer to take another treatment Can't be bothered Forget

Question 33

How to maximise compliance with treatments

Answer 33

Simplify instructions Ask about compliance Ask about effects and side-effects Monitor compliance and remind, etc...

Question 34

Give two interpretations of 'Is the new treatment better than the standard treatment?'.

Answer 34

Is **physiological action** of new treatment better than standard treatment? Is the new treatment better than the standard treatment in **routine clinical practice**?

Question 35

Explain the **Explanatory Trial:** **As-treated analysis.**

Answer 35

Analyses only those who completed the follow-up and complied with treatments. ## Footnote **Compares physiological effects of the treatments.**

Question 36

Disadvantages of Explanatory Trial: As-treated analysis.

Answer 36

Loses effects of randomisation where non-compliers are likely to be systematically different from compliers leading to **selection bias** and **confounding**.

Question 37

Explain pragmatic trail: Intention-to-treat analysis.

Answer 37

Analyses accodring to the **original allocation** to treatment groups regardless of follow-up or compliance. **Compares the likely effects of using the treatments in routine clinical practice** This means that it preserves the effects of randomisation.

Question 38

Differences between As-treated and Intention-To-Treat analyses.

Answer 38

As-Treated analyses tend to give **l****arger sizes of effect.** Intention-To-Treat analyses tend to give **smaller** and more **realistic sizes of effect**. This means that clinical trials should normally be **intention-to-treat.**

Question 39

Give examples of what is important to think of in order to get a good RCT.

Answer 39

Randomisation Blinding Intention-to-treat

Question 40

What is collective ethic?

Answer 40

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

Question 41

What is individual ethic?

Answer 41

Principle of **beneficence** (Will my clinical trial benefit patients?) Priniciple of **non-maleficence** (Will my clinical trials hurt anyone?) Principle of **autonomy** (Can I guarantee patient choice?) Priniciple of **justice** (Is my clinical trial just?)

Question 42

Explain individual ethics concerning RCTs.

Answer 42

RCTs may not guarantee benefit RCTs may result in harm RCTs may allocate treatment by chance RCTs may place burdens and confer benefits

Question 43

Explain clinical equipoise.

Answer 43

When there is reasonable **uncertainty** or **genuine ignorance** about the better treatment or intervention.

Question 44

Issues with clinical equipoise.

Answer 44

Is the uncertainty or ignorance by the **individual clinician** or the scientific community as a whole? What constitutes reasonable uncertainty? How is 'better' defined for the individual patient or for society as a whole?

Question 45

Explain why an RCT should be scientifically robust.

Answer 45

Adress a relevant or important issue Ask a valid question Can justify use of the comparator treatment or placebo

Question 46

Explain issues with ethical recruitment of **inclusion**.

Answer 46

Participants from communities that are **unlikely to benefit**. E.g. AIDS drug trials in developing world countries. Participants with a **high risk of harm** with respect to potential benefits. E.g. pregnant women. Participants likely to be excluded from analysis. E.g. a small sub-group of Chinese

Question 47

Explain issues with ethical recruitment of inapproriate exclusion.

Answer 47

People who differ from an **ideal homogenous** group. E.g. non-white, women, co-morbidities People who are difficult to get valid consent from. E.g. immigrants, mentally ill, children, prisoners

Question 48

What does valid consent consist of?

Answer 48

**Knowledgeable informant** Appropriate information **- verbal and written consent, a cooling off period, freedom to opt out** An informed participant, competent decision maker and a legitimate authoriser.

Question 49

Is signed consent valid consent?

Answer 49

Signed consent form as **evidence of valid consent** but it does not **equate to valid consent**.

Question 50

Explain voluntariness.

Answer 50

A pre-requisite for consent to be valid. The decision should be free from **coercion** or **manipulation** or the perception that coercion or manipulation may take place. **Perceived coercion or manipulation** invalidates consent as much as actual coercion or manipulation.

Question 51

Give examples of coercion.

Answer 51

Non-access to best treatment Lower quality of care Disinterest by clinician

Question 52

Give examples of manipulation.

Answer 52

Exploitation of emotional state Distortion of information Financial inducements

Question 53

Give another issue of voluntariness.

Answer 53

If undue influence is being exerted causing the potential participant to act in an uncharacteristical way then that influence is regarded as unethical.

Question 54

What do research ethics committees focus on?

Answer 54

Scientific design and conduct of the study Recruitment of participants Care and protection of participants Protection of participant's confidentiality Informed consent process Community considerations