1.3 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 and efficacy and safety
Define efficacy
The ability of a healthcare intervention to improve the health of a defined group under specific conditions
Define safety
The ability of a healthcare intervention not to harm a defined group under specific conditions
Efficacy vs effectiveness
Efficacy- measured in ideal clinical conditions, mostly used by pharmaceutical companies
Effectiveness- real world clinical experience, more significant for clinicians
What 3 things does a clinical trial need to be? And why?
Reproducible
Controlled- so that the effects of the new treatment are isolated and can confirm the outcomes are down to the treatment
Fair- unbiased
What are the stages of drug development?
Preclinical -> 1. Volunteer studies –> 2. Treatment studies –> 3. Clinical trials –> 4. Post marketing surveillance
Explain the disadvantages of comparison with historical controls
Selection often less well defines
Less info available about potential bias or confounders
Lack of control of the other treatments provided by the hospital
Hospital care changes with time
Populations change with time
Explain the disadvantages of non randomised clinical trials
Allocation bias and confounding variables
Hospital management might be different
Populations might be varying e.g. ethnicity
Outline the steps involved in a randomised controlled trial
Definition of key study variables
Conduct of the trial
Comparison of the outcomes
RCT: step 1 Define
Define:
The disease of interest and which patients would be eligible
Which treatments are being compared e.g. 2 drugs or vs a placebo
What outcomes are being measures
Are there any possible biases or confounders
RCT: Step 2 Conduct of the trial
Identify and invite a source of eligible patients with consent
Allocate patients fairly
Follow up in identical ways
Minimise losses to follow up and maximise adherence
RCT Step 3 Comparison of outcomes
Statistically significant? CLincially significant? Good design?
Why do we need to have ore-defining outcomes?
It prevents data dredging and repeating analyses, it is protocol for data collection and have agreed criteria
What is the difference between primary and secondary outcomes?
Primary- used in the sample size calculation and tends to be mortality. Mortality is the most common used by companies
Secondary- Eg QOL, ejection fraction
Types of outcomes
Patho-physiological e.g. tumour size, thyroxine levels
Clinical e.g. death, disease, disability
Patient focused e.g. QoL, psychological well-being, social well-being, satisfaction
Features of an ideal outcomes
Appropriate and relevant Valid and attributable Sensitive and specific Reliable and robust Simple and sustainable Cheap and timely
What does random allocation allow?
Minimal allocation bias and minimal confounding variable, works for known and unknown variables
What is a confounder?
A confounder is a factor associated with the exposure and is independently a risk factor of the disease
What are the most common confounding variables
Age and sex
What effect can knowing the treatment allocation have on the trial? How does it effect the three parties of the trial?
May bias the results.
Patients- behaviour effect
Clinician- non treatment effect
Investigator- measurement bias
How can we avoid allocating bias?
Blinded trials
Describe the placebo effect
Even if the therapy is irrelevant to the patients condition, the patients attitude to his or her illness, and indeed the illness itself, may be imoirced by a feeling that something is being done about it.
What is a placebo, what is its function?
An inert substance made to appear identical to treatment which it is compared to.
The aim is to cancel out placebo effect
What are the ethical implications of a placebo?
It should only be used in the absence of standard treatment
Use of a placebo is a form of deception
Therefore patients must be informed they may be receiving a placebo
How does one overcome losses to follow up?
Make the follow up practical and minimise inconvenience
Be clear and honest about the commitment required from participants
Avoid coercion or inducements
Maintain contact with patients
How does one overcome non-compliance with treatments
Simplify the instructions
Ask abut compiance
Ask about effects and side effects
What are reasons for non-compliance?
May have misunderstood instructi9ons May not like their treatment May think their treatment is not working May switch to other treatment Cant be bothered
What is an explanatory trial also known as?
‘As treated’ analysis
Describe explanatory trials:
Analyses only those who completed the follow up and complied with treatment and compares the physiological effects of the treatments
What is the disadvantage of explanatory trials
Loses the effects on randomisation as the non compilers are likely to be systematically different to the compliers so there is selection bias and confounding
What is a pragmatic trial also known as?
Intention to treat analysis
Describe pragmatic trials
Analyses according to the original allocation to treatment groups regardless of compliance or follow pu and compares the likely effects of using treatment in routine clinical practice
PRESERVES RANDOMISATION
‘As treated’ vs ‘Intention to treat’
As treated analyses tend tp give larger sizes of effect
Intenti0on to treat analyses tend to give snakier and fire realistic size of effect- this is the preferred option
Declaration of Helsinki 2013
“The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”
What is collective ethic?
All patients should have treatments that are properly tested for efficacy and safety
What is individual ethic?
Beneficiance
Non Maleficience
Autonomy
Justice
What are the issues that should be considered for a clinical trial to be ethical?
Clinical equipoise- when there is reasonable uncertainty to genuine ignorance about the better treatment or intervention
Scientifically robust- addresses the question
Ethical recruitment
Valid consent
Voluntariness
