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Flashcards in Randomised Controlled Trials Deck (56):

Define a clinical trial.

An experiment in which a treatment is administered to humans in order to evaluate its efficacy and safety.


What are the three types of clinical trials?

An uncontrolled trial
A controlled trial
A randomised controlled trial


What is an uncontrolled trial?

Everyone gets the treatment


What is a controlled trial?
What may the controls be?

A treated group is compared with an untreated group (placebo)
Or a treated group is compared with a control group having “usual/current gold standard treatment”
Controls may be geographical, historical, or randomised.


What is a randomised controlled trial?

Allocation to groups is determined by chance


What is a geographical control? What bias might this cause?

Patients with the same disorder seen at another hospital or clinic where the new intervention is not provided
Selection bias


What is a historical control? What bias might this result in?

Patients with the same disorder seen in the past before the use of the new intervention
Selection bias


How do we randomise in RCTs? When is this done?

Not by alternate allocation as this might be predicted by patients or clinicians
Computer-generate the randomisation of allocations in treatment vs control group
After they are determined eligible


What is allocation bias?

Big difference between treatment and control group


What are benefits of randomised controls? (3)

- Helps ensure group receiving treatment A is similar to group receiving treatment B
- Avoids selection/allocation bias
- The only systematic difference between treatment and control groups is the treatment itself (hopefully)


How many kinds of blinding are there? What are they?

Single and double


What is the difference between single and double blind?

Single blind – patients do not know what treatment they are on
Double blind – also the observers do not know what treatment the patients are on (not always possible), not possible if surgical treatment for example


What are the two types of RCT?



When is parallel used? How many % of trials does this make up?

When effect of treatment is not reversible
About 85%


When is cross-over used?

When effect of treatment is reversible


Describe a parallel group RCT.

Randomise individuals into one of two groups (treatment A and treatment B). You then follow them up over time and record the outcome.


Describe a crossover group RCT.

You randomise the treatment sequence. Half of people receive treatment A first and the other half treatment B. You follow them up over time and record the outcome, THEN you switch it over so they have swapped to receive the other treatment. You follow them up over time again and record the outcome.


What are the advantages of cross-over trials? (3)

- Each patient is their own control
- Smaller sample size to get same number of observations
- Better for subjective measurements e.g. pain


What are the disadvantages of cross-over trials? (2)

- More time consuming (takes twice as long to run)
- Carry-over effects – carry over effect of one treatment into the other treatment period


What is a cluster randomised trial?

Randomise pre-existing groups (such as villages, schools, GP practices, rather than individuals) to one of two treatments. You follow them up over time and record the outcome.


What are the advantages of a cluster randomised trial? (2)

- Avoids contamination (all participants in the trial are affected by intervention even if only some receive it)
- Enhances compliance (e.g. due to community spirit)


Why are factorial trials done?

To assess 2 interventions using the same number of patients as 1 intervention
Usually little or no interaction between the two interventions


What is the aim of a non-inferiority trial?

Aims to show a new intervention is no worse than a current intervention e.g. but is cheaper
Analysis based on confidence interval only
Does confidence interval exclude non-inferiority margin (the maximum difference that can be tolerated)?


What are the phases in developing and evaluating a new drug? (6)

Phase 0
Phase 1
Phase 2
Phase 3
Phase 4


What is the PRECLINICAL phase? What is done and why?

Non-human study
In vitro and in vivo animal experiments to obtain preliminary efficacy, toxicity and pharmacokinetic information.


What is phase 0? What is done and why?

First in-human trials
Small number of subjects given subtherapeutic dose of drug to determine pharmacodynamics and pharmacokinetics.


What is phase 1? What is done and why?

Screening for safety
Testing of drug on (usually) healthy volunteers for dose ranging. Determine whether the drug is safe to check for efficacy.


What is phase 2? What is done and why?

Assess efficacy and safety
To determine whether drug can have a therapeutic effect. May be designed as case series or randomised controlled trial.


What is phase 3? What is done and why?

Assess efficacy and safety
Randomised controlled trial on large number of patients to determine what the therapeutic effect is.


What is phase 4? What is done and why?

Post-marketing surveillance
Safety surveillance (pharmacovigilance)


How long does this process of evaluating a new drug take?

Preclinical to Phase 4 can take 12-18 years


All trials must be registered prospectively. Where must they be registered?

One of the primary registries in the WHO network or the United States’ clinicaltrials.gov


How many primary registries are there in the WHO registry network? Give some examples.

International Standard Randomised Controlled Trial Number (ISRCTN)
European Union Clinical Trials Register (EU-CTR)
Australian New Zealand Clinical Trials Registry


What are the advantages of registries? (9)

- Assist in the planning of new trials
- Avoid unnecessary duplication of research
- Avoid subjecting patients to trials seeking evidence that is already available
- Encourage collaboration between research groups
- Facilitate optimal use of research funds by funding agencies
- Facilitate patients’ access to information and improve recruitment
- Improve opportunities for methodological research
- Reduce discrepancies between published results and original trial protocol
- Help to detect publication bias in meta-analyses


What is the risk of death in treatment group?

Number of deaths in treatment group/number of patients in treatment group


What is the risk of death in the control group?

Number of deaths in control group/number of patients in control group


What is the RR of death in the treatment group compared to control group?

Risk of death in treatment group/risk of death in control group


If the treatment has no effect, what is the relative risk?



Which is the correct interpretation of a relative risk of 0.86?

Those in the treatment group were 14% less likely to die/get disease than those in the control group.


What is intention-to-treat analysis?

Comparison of all subjects based on the treatment group assigned, regardless of whether they complied
It is the primary analysis.


What is on-treatment analysis?

Comparison of subjects who actually took treatment


What does poor compliance lead to?

On an intention-to-treat analysis reduces ability to detect treatment difference (if one exists)


How can we maximise compliance? (3)

Selection of patients (not too ill)
Double blind design
Run-in period where all get treatment (to identify those who can’t tolerate it)


What is meant by number needed to treat?
How is it calculated?

How many patients would need to be treated to prevent one patient getting the disease/disorder?
Calculate the risks for each group, then use these to calculate the absolute difference in risk (minus them from each other).
Number needed to treat = 100/absolute diff in risk


Why is sample size important? What happens if there are too few participants?

If too few participants may not detect a real effect: study does not have enough statistical power.


How is number needed calculated?

Based on some prior information (e.g expect relative risk of death of treatment A compared to B to be 2)


What is the power to be able to detect a difference usually set at?

85% (or at least 80%)


Statistically significant if 95% confidence interval for relative risk does not include...?



Statistically significant if p-value...?



What is the purpose of meta-analyses?

To bring together all the evidence to more powerfully estimate the effect size


What type of plot are the results of individual studies and a summary estimate often shown in?

Forest plot


What are the two main issues with meta-analyses?

Heterogeneity (variation in study results)
Publication bias


What causes heterogeneity? (4)

difference in study design
difference in participant characteristics
difference in intervention e.g. drug dose
chance alone


What is meant by publication bias?

Studies with significant or favourable results more likely to be published


What causes publication bias? (3)

journal editors
journal peer reviewers


How can publication bias be assessed graphically?

Funnel plot