Session 1: Clinical Trials Flashcards
Definition of a clinical trial.
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.
What is the purpose of a clinical trial?
To provide reliable evidence of treatment efficacy and safety.
Define efficacy.
The ability of a health care intervention to improve the health of a defined group under specific conditions.
Define safety
The ability of a health care intervention not to harm a defined group under specific conditions.
In order to be able to give a fair comparison of effect and safety, what does a clinical trial need to be?
Reproducible
Controlled (comparison of interventions)
Fair (unbiased)
What are clinical trial vulnerable to?
Random variation (chance)
How is chance reduced?
By increasing sample size
What is the difference between efficacy and effectiveness?
Efficacy = ideal clinical conditions (sterile)
Effectiveness = real world clinical experience (reality)
Give the different stages in drug development.
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
Explain the disadvantages of non-randomised clinical trials.
Allocation bias by patient, clinician or investigators
Confounding factors
Explain the disadvantages of comparison with historical controls.
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
Explain the steps in a RCT conducting the trial.
Eligible patients
Invite patients
Consent
Allocate treatment fairly (no bias, no confounding)
Follow-up (also minimise losses)
Maximise adherence to treatments
Reasons for Pre-defining outcomes
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.
What are primary outcomes?
Preferably only one primary outcome of your desired effect.
This is used in the sample size calculation.
E.g. mortality
What are secondary outcomes?
Other outcomes of interest that may appear in the clinical trial.
They often include occurrence of side-effects.
Give examples of types of outcomes.
Patho-physiological (tumour, thyroxine levels, ECG changes)
Clinical defined (death, disease, disability)
Patient-focused (quality of life, psychological well-being, social well-being, satisfaction)
Give examples of an ideal outcome.
Appropriate and relevant
Valid and attributable
Sensitive + specific
Reliable and robust
Simple and sustainable
Cheap and timely
Why is the timing of measurement important?
Using a baseline in order to monitor inadvertent differences in groups.
Monitor the possible effects as well as monitoring for adverse effects.
Final measurements
What are the issues with non-random allocation?
Selection bias
Confounding factors
What are the advantages of random allocation?
Minimal allocation bias
Minimal confounding factors
Issues with knowing the treatment allocation.
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)
Give an example of minimising allocation bias.
Blinding/masking
Give examples of blinding.
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)
Examples where blinding is difficult.
Surgical procedures
Psychotherapy
Alternative medicine
Lifestyle interventions
Prevention programmes
Advantages of blinding
Reducing selection bias
Reducing recall or reporting bias
Reducing observer bias
Explain the placebo effect
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.
What is a placebo?
An inert substance made to appear identical in every way to the active formulation with which it is compared to.
What is the aim of a placebo?
To cancel out any placebo effect that may exist in the active treatment.
Ethical implications of placebo.
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.
Give different losses to follow-up.
Appropriate loss of follow up (clinical condition may necessitate removal from trial)
Unfortunate loss of follow up (patient may choose to withdraw)
How to minimise losses to follow up.
Make follow-up practical and convenient
Be honest about commitment required
Avoid coercion or inducements
Maintain contact
Give examples of non-compliance
Misunderstanding of instructions
Not like treatment
Treatment not working
Prefer to take another treatment
Can’t be bothered
Forget
How to maximise compliance with treatments
Simplify instructions
Ask about compliance
Ask about effects and side-effects
Monitor compliance and remind, etc…
Give two interpretations of ‘Is the new treatment better than the standard treatment?’.
Is physiological action of new treatment better than standard treatment?
Is the new treatment better than the standard treatment in routine clinical practice?
Explain the Explanatory Trial: As-treated analysis.
Analyses only those who completed the follow-up and complied with treatments.
Compares physiological effects of the treatments.
Disadvantages of Explanatory Trial: As-treated analysis.
Loses effects of randomisation where non-compliers are likely to be systematically different from compliers leading to selection bias and confounding.
Explain pragmatic trail: Intention-to-treat analysis.
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.
Differences between As-treated and Intention-To-Treat analyses.
As-Treated analyses tend to give larger 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.
Give examples of what is important to think of in order to get a good RCT.
Randomisation
Blinding
Intention-to-treat
What is collective ethic?
All patients should have treatments that are properly tested for efficacy and safety.
What is individual ethic?
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?)
Explain individual ethics concerning RCTs.
RCTs may not guarantee benefit
RCTs may result in harm
RCTs may allocate treatment by chance
RCTs may place burdens and confer benefits
Explain clinical equipoise.
When there is reasonable uncertainty or genuine ignorance about the better treatment or intervention.
Issues with clinical equipoise.
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?
Explain why an RCT should be scientifically robust.
Adress a relevant or important issue
Ask a valid question
Can justify use of the comparator treatment or placebo
Explain issues with ethical recruitment of inclusion.
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
Explain issues with ethical recruitment of inapproriate exclusion.
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
What does valid consent consist of?
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.
Is signed consent valid consent?
Signed consent form as evidence of valid consent but it does not equate to valid consent.
Explain voluntariness.
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.
Give examples of coercion.
Non-access to best treatment
Lower quality of care
Disinterest by clinician
Give examples of manipulation.
Exploitation of emotional state
Distortion of information
Financial inducements
Give another issue of voluntariness.
If undue influence is being exerted causing the potential participant to act in an uncharacteristical way then that influence is regarded as unethical.
What do research ethics committees focus on?
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
