2 Clinical Trials

Question 1

Identify the different stages in drug development as well as their associated duration

Answer 1

• Discovery research (4 years)
• Phase 1 (1 year)
• Phase 2 (2 years)
• Phase 3 (4 years)
• Regulatory review (1 year)
• Phase 4

Question 2

With reference to drug action, what does the statement ‘scientifically proven to work’ mean?

Answer 2

“It is better than the other treatment” i.e. more people receiving this treatment are cured than those on the other treatment

Question 3

What is a clinical trial?

Answer 3

A clinical trial is 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 4

What is the purpose of a clinical trial? Differentiate between the terms efficacy and safety in the context of a clinical trial.

Answer 4

The purpose of a clinical trial is to provide reliable evidence of treatment efficacy and safety

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

Safety: 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, which three features must a clinical trial have?

Answer 5

• Reproducible – in experimental conditions
• Controlled – comparison of interventions
• Fair – unbiased without confounding

Question 6

What are non-randomised clinical trials?

Answer 6

Non-randomised clinical trials involve the allocation of patients receiving a new treatment to compare with a group of patients receiving the standard treatment

Question 7

What are the two disadvantages and the advantage of non-randomised clinical trials?

Answer 7

Disadvantages:

• Allocation bias – by patient, clinician or investigator
• Confounding – known and unknown

Advantage:

-Convenient and easy to carry out

Question 8

What are the three steps involved in a randomised controlled trial (RCT)

Answer 8

1. • Definition of factors
2. • Conduction of the trial
3. • Comparison of outcomes

Question 9

Identify the 6 factors which need to be defined in an RCT

Answer 9

• 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 10

What are the seven sub-steps in conducting a RCT?

Answer 10

⇒ Identify a source of eligible patients

⇒ Invite eligible patients to be in the trial

⇒ Consent patients willing to be in the trial

⇒ Allocate participants to the treatments fairly, i.e. without bias or confounding

⇒ Follow-up participants in identical ways

⇒ Minimise losses to follow-up

⇒ Maximise compliance with treatments

Question 11

Which four questions might one ask when comparing outcomes in an RCT?

Answer 11

• 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? ie consider confoundings

Question 12

Identify three types of clinical outcomes and provide examples for each

Answer 12

• Patho-physiological e.g. tumour size, thyroxine level, ECG changes
• Clinically defined e.g. mortality, morbidity, disability
• Patient-focused e.g. quality of life, psychosocial well-being, satisfaction

Question 13

Describe the timing of measurements in a clinical trial

Answer 13

• Baseline measurement of relevant factors – monitoring for inadvertent differences in groups
• Monitoring outcomes during the trial – monitoring for possible effect / adverse effects
• Final measurement of outcomes – comparing final effect of treatments in trial

Question 14

What are the two advantages of random allocation?

(works well with large groups- less well with small groups)

Answer 14

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

Question 15

Blinding/masking is a method to ensure minimal allocation bias.

What are the two types of blinding?

Answer 15

• Single blind – one of: patient, clinician, assessor does not know the treatment allocation
• Double blind – two of: patient, clinician, assessor does not know the treatment allocation (usually patient + clinician/assessor)

(Can have triple blind studies)

(usually patient)

Question 16

Identify five situations where blinding is difficult to achieve

Answer 16

• Surgical procedures
• Psychotherapy vs. anti-depressant
• Alternative medicine vs. Western medicine
• Lifestyle interventions
• Prevention programmes

Question 17

What is the placebo effect?

Answer 17

The Placebo Effect – “even if the 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 18

What is a placebo?

Answer 18

A placebo is an inert substance made to appear identical in every way to the active formulation with which it is to be compared e.g. appearance, taste, texture, dosage regime, warnings, etc

Question 19

What is the purpose of a placebo?

Answer 19

The aim of a ‘placebo’ is to cancel out any ‘placebo effect’ that may exist in the active treatment

Question 20

The use of a placebo is a form of deception.

Hence, what are the ethical implications for this?

Answer 20

• A placebo should only be used when no standard treatment is available
• Participants in a placebo-controlled trial are informed that they may receive a placebo

Question 21

What leads to losses to follow-up i.e. not every participant remains in the clinical trial? (2)

Answer 21

• Their clinical condition may necessitate their removal from the trial (appropriate)
• They may choose to withdraw from the trial (unfortunate)

Question 22

Suggest four ways that might help minimise losses to follow up in clinical trials

Answer 22

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

Question 23

What leads to non-compliance to treatment in patients?

Answer 23

• They may have mis-understood the instructions
• They may not like taking their treatment
• They may think their treatment is not working
• They may prefer to take another treatment

Question 24

Suggest four ways that might help maximise compliance with treatments

Answer 24

• Simplify the instructions
• Ask about compliance
• Ask about effects and side-effects
• Monitor compliance e.g. tablet count, urine level, blood level

Question 25

Explain how one might conduct an explanatory trial – 'as-treated’ analysis

Answer 25

- Analyses only those who **completed follow-up** and **complied with treatments** - Compares the **physiological effects** of the treatments BUT- Loses effects of **randomisation** → selection bias and confounding

Question 26

Explain how one might conduct a pragmatic trial – 'intention-to-treat’ analysis

Answer 26

- Analyses according to the **original allocation** to treatment groups, **regardless of compliance/completion** - Compares the **likely effects** of using the treatments in **routine clinical practice** - Preserves effects of **randomisation** → minimal selection bias and confounding

Question 27

Clinical trials should normally be analysed on an ‘intention-to-treat’ basis. Why is this?

Answer 27

- **'As-Treated’** analyses tend to give larger sizes of effect - **‘Intention-to-Treat’** analyses tend to give smaller and more realistic sizes of effect

Question 28

What is the principle of collective ethic?

Answer 28

**Collective ethic** – all patients should have treatments that are properly tested for efficacy and safety

Question 29

What are the principles of individual ethic?

Answer 29

- The principle of **beneficence** - The principle of **non-maleficence** - The principle of **autonomy** - The principle of **justice**

Question 30

Explain collective ethic vs individual ethic in terms of randomised controlled trials

Answer 30

**_Collective ethic_** – RCTs aim to properly test treatments for efficacy and safety **_Individual ethic-_** - RCTs do not **guarantee benefit** - RCTs may result in **harm** - RCTs allocate treatment **by chance** - RCTs place **burdens** and confer **benefits**

Question 31

What is clinical equipoise?

Answer 31

**Clinical equipoise** is when there is reasonable uncertainty or genuine ignorance about the better treatment or intervention (including non-intervention)

Question 32

Which 8 features make a trial scientifically robust?

Answer 32

- Addresses a **relevant issue** - Asks a **valid question** - Has an **appropriate study design** and protocol - Has the potential to **reach sound conclusions** - Can justify the use of the **comparator treatment or placebo** - Has **acceptable risks of possible harm** compared to anticipated benefits - Has provision for **monitoring the safety** participants - Has **arrangements for appropriate reporting** and publication

Question 33

In terms of ethical recruitment, provide two scenarios demonstrating inappropriate exclusion

Answer 33

- People who differ from an **ideal homogenous group** *e.g. non-White people, women, co-morbidities (usually elderly)* - People who are difficult to get **valid consent from** *e.g. immigrants, mentally ill, children, prisoners*

Question 34

In terms of ethical recruitment, provide two scenarios demonstrating inappropriate inclusion

Answer 34

- Participants from communities that are **unlikely to benefit** *e.g. AIDS drugs trials in LEDCs* - 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 35

Describe the six steps involved to attain valid consent

Answer 35

⇒ Knowledgeable **informant** ⇒ Appropriate **information** (verbal, written, freedom to opt out) ⇒ Informed **participant** ⇒ Competent **decision-maker** ⇒ Legitimate **authoriser** ⇒ Signed **consent form** as evidence of valid consen

Question 36

What is voluntariness?

Answer 36

**Voluntariness** is a pre-requisite for consent to be valid, i.e. the decision should be free from *coercion or manipulation*

Question 37

Perceived coercion or manipulation invalidates consent as much as actual coercion or manipulation. Provide some examples of coercion

Answer 37

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

Question 38

Perceived coercion or manipulation invalidates consent as much as actual coercion or manipulation. Provide some examples of manipulation

Answer 38

- Exploitation of emotional state - Distortion of information - Financial inducements

Question 39

Differentiate between efficacy and effectiveness. (in terms of prescribing and clinical trials)

Answer 39

Efficacy: results in ideal clinical conditions Effectiveness: results in real world clinical experience (more realistic)

Question 40

Apart from randomised control trials, what is the best for of evidence?

Answer 40

Meta analysis- from lots of data

Question 41

What are the features of an 'ideal outcome'?

Answer 41