1.3+4 Population Science Clinical Trials Flashcards
What do phase 1 studies detect?
Pharmacodynamics
Pharmacokinetics
Major side effects
What do phase 2 studies aim to detect?
Effects and dosages
Common side effects
What do phase 4studies aim to detect?
Monitoring for adverse reactions
Potential new uses
What type of risk does scientifically proven refer to?
Relative risk
What type of study are clinical trials?
Cohort study
Exposed and unexposed then count outcome events and person years
So do new treatments and standard treatment and then measure the outcomes over time
Define a clinical trial
Any for, 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
What does a Control in a clinical trial mean?
It means that there is a comparison
NOT that everything is controlled
What three things should a clinical trial be to be able to give a fair comparison of effect and safety?
Reproducible
Controlled
Fair
What does the observed rate ratio mean?
If the null hypothesis value is consistent with the observed data, then any observed difference from the null hypothesis may be due to chance
What is randomisation?
Having an equal chance of being put into group A or group B
What do non randomised clinical trials involve?
The allocation of patients receiving a new treatment to compare with a group of patients receiving the standard treatment
What are two problems with non randomised clinical trials?
Allocation bias
Confounding (known and unknown)
What is a benefit of RCT in terms of confounding?
Randomising reduces confounding
This includes confounding factors that were unknown at the time
This works as long as the sample size was large enough
What are some of the issues with the standard treatment group when using historical controls?
Selection often less well defined and less rigorous
Treated differently from new treatment group
Less information about bias and confounders
Unable to control for confounders
What factors must be controlled in a RCT?
Disease of interest Treatments to be compared Outcomes to be measured Possible bias and confounders The patients eligible for the trial The patients to be excluded from the trial
What steps are involved for conduct of the trial?
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
Follow up participants in identical ways
Minimise losses to follow up
Maximise compliance with treatments
How can you tell if a trial is statistically significant?
Could the observed difference have originated by chance?
Related to p value and 95% confidence interval
How can you tell whether a trial is clinically important?
How big is the observed difference between the treatment groups?
Need to have a big enough study group
Why do you need to predefine outcomes for a clinical trial?
Prevent data dredging and repeated analyses
Protocol for data collection
Agreed criteria for measurement and assessment of outcomes
What is data dredging?
Looking back at studies, at very small groups, to find an effect
What is the primary outcome used in?
Sample size calculation
What are three groups of outcomes?
Pathophysiological
Clinically defined
Patient focussed
Name some pathophysiological outcomes?
Tumour size
Thyroxine level
ECG changes
Name some clinically defined outcomes
Death (mortality)
Disease (morbidity)
Disability
Name some patient focussed outcomes
Quality of life
Psychological well-being
Social well being
Satisfaction
What are some features of an ideal outcome?
Appropriate and relevant
Valid and attributable - any observed effect can be reasonably be linked to compared treatments
Sensitive and specific
Reliable and robust- outcome measurable by different people in different settings
Simple and sustainable - method of measurement easily carried out repeatedly
Cheap and timely
What is non random allocation?
Allocation of participants to treatments by a person, historical basis, geographical location, convenience, numerical order
What is a problem with non random allocation?
Leads to the potential for allocation [aka. selection] bias and confounding factors to unwittingly cause unidentified differences between the treatment groups being compared
Non random allocation -> allocation bias and confounding
What are the advantages of random allocation?
Minimal allocation bias
- Each participant has an equal chance of being allocated to either treatment
Minimal confounding
- Treatment groups likely to be similar in size and characteristics by chance
For known and unknown factors
What is the issue with open label?
Knowledge of which participant is receiving which treatment may bias the results of a clinical trial
What is a behaviour effect?
Patient may alter their behaviour, other treatment, or expectation of outcome due to open label trial
What is the non treatment effect?
Clinician may alter their treatment, care and interest in the patient in an open label trial
What is measurement bias?
Investigator may alter their approach when making measurements and assessing outcomes in open label trials
What are some examples of where blinding may be difficult?
Surgical procedures Psychotherapy vs antidepressant Alternative medicine vs western medicine Lifestyle interventions Prevention programmes
What is 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
What is a placebo?
An inert substance made to appear identical in every way to the active formulation with which it is being compared
Eg appearance, taste, texture, dosage regime, warnings
What is the aim of a placebo?
Cancel out any placebo effect
What are the ethical implications of placebo?
A placebo should only be used when no standard treatment is available
Use of placebo is a form of deception
All participants should be told they may get a placebo
What are the two types of losses to follow up?
Appropriate- Their clinical condition may necessitate their removal from the trial
Unfortunate - They may choose to withdraw from the trial
How can you minimise losses to follow up?
Make follow up practical and convenient
Be honest about the commitment required from participants
Avoid coercion or inducements
Maintain contact with participants
Why may some patients be non compliant?
Mis understoo instructions Not like taking treatment Think treatment doesn’t work Cant be bothered Prefer other treatments
How can compliance be maximised?
Simplify instructions
Ask about compliance
Ask about effects and side effects
Monitor compliance eg tablet count, urine and blood levels
What is as treated analysis?
Analyse according to whether they took the treatment
This is an explanatory trial
Analyses only those who completed follow up and complied with treatments
Compared the physiological effects of the treatments
What is the problem with an explanatory trial?
Looses effect of randomisation
Non compilers likely to be systematically different from compliers leading to selection bias and confounding
What is intention to treat analysis?
Analyses according to the original allocation to treatment groups regardless of whether they completed follow up and complied
Compares the likely effects of using the treatments in routine clinical practice
Includes people that didn’t take the treatment as don’t know if people who took the treatment definitely took it
What is the advantage of a pragmatic trial?
Preserves effects of randomisation so minimal selection bias and confounding
What are the impacts on size of effect for as treated vs intention to treat
As treated give larger sizes of effect
Intention to treat give smaller more realistic sizes of effect
What type of analysis should clinical trials use?
Intention to treat
What is collective ethic?
All patients should have treatments that are properly tested for efficacy and safety
What is individual ethic?
The principles of beneficence, non-maleficence, autonomy and justice
Who do RCTs benefit?
Future patients
Why do RCTs not display individual ethic?
They do not guarantee benefit
They may result in harm
They allocate treatment by chance
They place burdens and confer benefits
What issues should be considered for a clinical trial to be ethical?
Clinical equipoise Scientifically robust Ethical recruitment Valid consent Voluntariness
What is clinical equipoise?
when there is reasonable uncertainty or genuine ignorance about the better treatment or intervention (including non- intervention)
What factors contribute to making a trial scientifically robust?
Addresses relevant or important issue
Asks a valid question
Appropriate study design and protocol
Can justify use of the comparator treatment or placebo
Acceptable risks of possible harm compared to anticipated benefits
Provision for monitoring the safety and well being of trial participants
Arrangements for appropriate reporting and publication
What are the two issues surrounding ethical recruitment?
Inappropriate INCLUSION of
- people unlikely to benefit
- people with a high risk of harm compared to benefits eg pregnant women
- people likely to be excluded from analysis eg small sub groups
Inappropriate EXCLUSION of
- people who differ from ideal homogenous group eg co morbidity, elderly
- people who are difficult to get valid consent from eg immigrants, children, mentally ill
What things are required to gain valid consent?
Knowledgeable informant
Appropriate information with cooling off period
Informed participant who is a competent decision maker and a legitimate authoriser
When may a signed consent form not equate to valid consent?
If it can be shown that the explanation was not adequate or if there was coercion
What are some examples of coercion?
Non access to best treatment, lower quality of care, disinterest by clinician
What are some examples of manipulation?
Exploitation of emotional state, distortion of information, financial inducements
