Randomised Controlled Trials Flashcards
What is the main difference between RCTs and case-control/cohort studies?
RCTs are EXPERIMENTAL whereas case-control/cohort studies are OBSERVATIONAL
What is meant my ‘intervention’ when applied to RCTs?
Prophylactic, diagnostic or therapeutic agents/devices/regimes/procedures - NOT JUST DRUGS
What is the purpose of a clinical trial?
To provide reliable evidence of treatment EFFICACY (improve health) and SAFETY (not to harm)
What must a clinical trial be in order to give a fair comparison of efficacy and safety?
- REPRODUCIBLE in experimental conditions
- CONTROLLED by comparison of interventions
- FAIR unbiased without confounding
Define a ‘non-randomised clinical trial’
ALLOCATION of patients receiving a new treatment to compare with a group of patients receiving the standard treatment
What are the disadvantages of using historical controls for a non randomised clinical trial?
- Selection is often LESS WELL DEFINED and LESS RIGOROUS than the selection of patients on the new treatment
- Selection may have been TREATED DIFFERENTLY from ‘new treatment group’
- LESS INFORMATION known about selection so cannot account for POSSIBLE BIAS/CONFOUNDING factors
What are the main disadvantages of non randomised clinical trials?
- ALLOCATION BIAS
- Confounding (known and unknown)
What effect do non randomised trials have on the result of efficacy of the new treatment?
OVERESTIMATE the benefits of the new treatment (almost always)
What factors need to be defined BEFORE starting a RCT?
- Disease of interest
- Treatments to be compared
- Outcomes to be measured
- Possible bias or confounders
- Patients eligible for trial
- Patients to be excluded from trial
Describe and explain how a RCT is conducted
- IICAFMM
- Identify eligible patients
- Invite eligible patients to be in trial
- Consent patients willing to be in trial
- Allocate participants to the treatments fairly (no bias or confounding)
- Follow up participants in identical ways equally
- Minimise losses to follow up
- Maximise compliance with treatments
What factors must you take into account when comparing the outcomes of treatments in the trial?
- How big is the observed difference (clinical importance)?
- Is the observed difference attributable to the compared treatments in the trial?
- Could the observed difference be due to chance (statistically significant)?
When would you use a placebo?
When there is no current (standard) treatment for the disease of interest
What is a placebo?
An INERT substance with looks, tastes and is packaged identically to the comparison drug
What is the main reason for randomisation in clinical trials?
AVOID ALLOCATION BIAS
What are the advantages of random allocation?
- Minimises allocation bias
- Minimises confounding as both groups should be evenly distributed regarding age, sex and social status
How are patients randomly allocated to a treatment?
- TOSS A COIN (heads is new treatment, tails is standard/placebo)
- RANDOM NUMBER GENERATOR (odd number is new treatment, even number is standard/placebo)
Why may differences in outcomes between treatments occur?
- CHANCE (small trials may have unbalanced and non-comparable groups so may be subjected to bias/confounding)
- PATIENT/CLINICIAN/ASSESSOR KNOW WHICH TREATMENT THE PATIENT HAS (may lead to amendment of behaviour by patient, different choice of secondary treatment by clinician or different approach in measurement of outcomes by assessor)
- ONE TREATMENT IS MORE EFFECTIVE THAN THE OTHER
What types of outcomes can be measured in an RCT?
- PATHOPHYSIOLOGICAL e.g. Tumour size, hormone levels
- CLINICALLY DEFINED e.g. Death, disability
- PATIENT FOCUSSED e.g. Quality of life, psychosocial wellbeing
Why do outcomes need to be defined BEFORE starting the trial?
- PREVENTS DATA DREDGING
- Protocol for data collection
- Agreed criteria for measurement and assessment of outcomes
Describe the monitoring of groups before, during and after the trial
- BEFORE - monitor for inadvertent differences between the groups
- DURING - monitor for possible or adverse effects (is one group disadvantaged or being harmed?)
- AFTER - monitor and compare the final effect of each treatment
What is meant by ‘non random allocation’?
Allocation of participants to treatments by historical basis, geographical location, convenience or numerical order i.e. ANY WAY WHICH IS NOT RANDOM
What is meant oh by ‘random allocation’?
Allocation of the treatments to participants equally and fairly
- MINIMISES ALLOCATION BIAS
- MINIMISES CONFOUNDING
Why does random allocation minimise confounding?
IN THE LONG RUN, randomisation leads to an even distribution of participants in each group in regards to age, sex and social status, therefore the RESULTS ARE LESS LIKELY TO BE DUE TO CHANCE
How could you increase the randomisation and fairness of a trial?
BLINDING/MASKING
Why are few trials triple blinded?
Clinician and assessor tend to be the same person
What is the advantage of blinding?
Aims to MINIMISE ALLOCATION BIAS by ensuring that each participant has an equal chance of being allocated to each of the treatments in the trial
Where might blinding be difficult?
- Surgical procedures
- Lifestyle interventions
- Alternative medicine
- Psychotherapy
- Prevention programmes
What is the placebo effect?
Patients attitude to their illness may be improved even if the treatment is irrelevant as THEY FEEL THAT SOMETHING IS BEING DONE ABOUT IT
What is the aim of using a placebo?
Cancel out any placebo effect that may exist in the active treatment
What are the ethical problems with using a placebo?
- FORM OF DECEPTION
- Participants must be informed before the trial that they may receive a placebo
Why might losses to follow up occur?
- Participant may choose to withdraw from the trial
- Participant’s clinical condition may worsen (become more ill or DEATH)
How could you minimise losses to follow up?
- Make follow up practical by minimising inconvenience
- Maintain contact with patients
- Be honest and open about commitment needed by patient at the start of the trial
- AVOID COERCION OR INDUCEMENT
Why may patients not comply with the allocated treatment?
- Misunderstood instructions
- Dislike taking treatment
- Think treatment is ineffective
- Prefer another treatment
- CBA
How could you maximise compliance with the treatment?
- Simple instructions
- Monitor compliance e.g. Tablet count, blood/urine level
- Give information before hand about possible side effects of treatments
What is the difference between EXPLANATORY and PRAGMATIC trials?
- Explanatory is AS TREATED where only those who complied with the treatment and were followed up are analysed
- Pragmatic is INTENTION TO TREAT where all participants are analysed regardless of compliance and follow up
What are the disadvantages of an AS TREATED analysis?
- LOSES THE EFFECT OF RANDOMISATION
- Non-compilers are likely to be systematically different than compilers (subject to selection bias and confounding)
- Leads to an OVERESTIMATE of the benefits of the new treatment
What are the advantages of using an INTENTION TO TREAT analysis?
- PRESERVES RANDOMISATION
- Minimal selection bias and confounding
Why do RCTs not respect the individual ethics?
- RCT ARE FOR THE BENEFIT OF FUTURE PATIENTS
- They do not guarantee to benefit the patient
- They may causes unknown harm
- Treatments are allocated by chance so removes autonomy
- May place burdens and confer benefits
What is the collective ethics stated for RCTs?
All patients should have treatments that are properly tested for efficacy and safety
What are the 4 criteria for individual ethics?
- Beneficence
- Non maleficence
- Autonomy
- Justice
What issues must be considered for an ethical clinical trial?
- CLINICAL EQUIPOISE
- Scientific robustness
- Ethical recruitment (fair)
- Valid consent
- Voluntariness
What is ‘clinical equipoise’?
There is a reasonable uncertainty about which treatment is better than the other
What is meant by a clinical trial being scientifically robust?
- Addresses a relevant issue
- Asks a valid question
- Has the potential to reach sound conclusions
- Has an appropriate design and protocol
- Has provision for monitoring the safety of the participants
What is meant by ‘ethical recruitment’?
- INAPPROPRIATE INCLUSION of participants who are not likely to benefit or have a high risk of harm from the new treatment
- INAPPROPRIATE EXCLUSION of participants due to race or difficultly in gaining valid consent
What factors must be taken into account when taking valid consent?
- Knowledgable informant
- Appropriate information and cooling off period
- Chance to opt out
- Informed participant
- Competent decision maker
Define 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 role of the Research Ethics Committee?
TO ENSURE THAT THE RESEARCH RESPECTS THE DIGNITY, RIGHTS, SAFETY AND WELLBEING OF THE INDIVIDUAL RESEARCH PARTICIPANTS
What is meant by ‘Voluntariness’ in a clinical trial?
- NO COERCION OR INDUCEMENTS
- Decision to enter trial must be free from manipulation
What criteria are used for outcome measures?
PRROVS
- Practical
- Reliable
- Relevant
- Objective
- Valid
- Sensitive/Specific
