L2 Clinical Trials Flashcards
Clinical trial
Planned experiment which involves patient’s and is designed to elucidate the most appropriate method of treatment for future patients with a given medical condition
Efficacy
Ability of an intervention to improve the health of a defined group under specific conditions
Aka effect
Safety
The ability of a health care intervention not to harm a defined group under specific conditions
Goals of clinical trial
Reproducible
Controlled - comparison of intervention
Fair - Unbias without confounding
Difference between efficacy and effectiveness
Effectiveness is the effect in real world clinical experience where as efficacy is in ideal condition
Stages in drug development and monitoring
Phase I
- volunteer studies
- assessing pharmacodynamics, pharmacokinetics and side effects
- healthy volunteers (controlled)
Phase II
- treatment studies
- effects and dosage - therapeutic window
- common side effects
- patients
Phase III
- clinical trials
- COMPARISON with standard treatment
- patients
Phase IV
- post marketing surveillance
- monitoring for adverse side effects
- potential for new uses
- whole population
Disadvantages of a non randomised clinical trial
Allocation bias - by patient, clinician or investigator
Confounding - known and unknown
Disadvantages of comparison with histological controls
Condition may have changed from the past
Population factors change with time
Different hospitals may have different protocols
Selection of histological controls are less rigorous
Histological controls were probably treated differently from new treatment group
Less information about potential bias of con founders
Steps involved in an RCT
- Definition of key study variables
- Clinical trial
- Compare outcomes
Defining the key variables
Define the:
- disease of interest
- patient eligible for the trial
- patients excluded from trial e.g. disease too advanced
- treatment to be compared
- outcomes to be measured e.g. adherence, hospital admission etc.
- possible bias or confounders
How to conduct a trial
Identify a source of eligible patients Invite those eligible Consent patients Allocate participants randomly Follow up patients Minimise losses to follow up Maximise adherence to treatments
Comparison of outcomes
Is there an observed difference
Statistically significant
Is the difference clinically significant
Was the design of the trial and conduct good
95% confidence interval
If the null hypothesis is within the 95% confidence interval, the results may be due to chance
P > 0.05
Therefore not statistically significant
Observed ratio of 0.87 meaning
Reduction of 13%
Sample size effect on confidence interval
Larger sample size, decreases the confidence interval
Why are outcomes predefined
Need to define what, when and how outcomes are measure before the clinical trial to:
- prevent repeated analyses
- define protocol for data collection
- agreed criteria for measurement and assessment of outcomes
Primary outcome
Most important outcome of interest e.g. mortality
Preferably 1 primary outcome
Used in the sample size calculation
Secondary outcomes
Other outcomes of interest
E.g. side effects or occurrence or quality of life
Types of outcomes
Pathophysiological:
- tumour size
- thyroxine levels
- ECG changes
Clinically defined:
- mortality
- disease
- disability
Patient focused:
- QoL
- psychological well-being being
- social well being
- satisfaction
Features of an ideal outcome
Appropriate and relevant Valid and attributable Sensitive and specific Reliable and robust Simple and sustainable Cheap and timely
Timing of measurements
Baseline:
- monitor for inadvertent differences in groups
During trial:
- possible effects - is one group more disadvantaged
- Adverse effects
After trial
- comparing final effect of treatment
Types of allocation
Non random allocation
Random allocation
Knowing the treatment allocation
Blinding
Disadvantages of knowing the treatment allocation
Knowledge of which patient is getting which treatment
- participant bias - behaviour effect
- clinician may alter their treatment - non treatment effect
- investigator may alter their approach when assessing outcomes - measurement bias
How to limit bias
Allocation bias - random allocation
Recall bias - use pathophysiological or clinical outcomes e.g. mortality
Observer bias - double blind
Single blind
1 of patient, clinician or investigator doesn’t know which treatment they’re receiving
Double blind
2 of patient, clinician or investigator doesn’t know allocation
Triple blind
All do not know treatment allocation
Placebo effect
A patient acts differently because of the treatment they receive
Therefore provide a placebo as a control to cancel out the placebo effect
Disadvantage of comparing treatment with no treatment
Do not know whether outcome is due to treatment or that one group received care
Ethical implications of a placebo
Should only be used when no treatment is available
Placebo is a form of deception
Important that participants are informed that they may receive the placebo
Losses to follow up
Not every participant remains in the trial as:
- their condition may make it necessary to be removed from the trial
- May choose to withdraw from the trial
- die before trial ends
How to minorities loss to follow up
- make follow up practical and minimise inconvenience
- honest about commitment required
- maintain contact with participants
Non compliance with treatment reasons
- misunderstood instructions
- May not like taking treatment
- May think treatment isn’t working
- prefer to take another treatment
- can’t be bothered
Reduce non compliance
- simplify instructions
- ask and monitor compliance
- ask about effects or side effects
Difference between explanatory and pragmatic trial
Explanatory
- ‘as treated’ analysis
- ignores participants that do not take treatment or loss to follow up
- biologists
- new treatment vs standard treatment
- compares physiological effects of the treatment
- larger sizes of effect
Pragmatic
- ‘intention to treat’ analysis
- includes non treated
- medics
- new treatment and not take new treatment vs standard treatment and not take standard treatment
- compares effects of use of treatment routinely
- preserves randomisation
- smaller more realistic sizes of effect
Disadvantage of explanatory as treated trials
Loss of randomisation as those that do not comply are likely to be systemically different from compilers
- selection bias
- confounding
Declaration of Helsinki
Health of the patient is the upmost priority
Act only in the patients interest
Collected ethic
All patients should have treatments that are properly tested for efficacy and safety
- RCTs aim to properly test treatment for efficacy and safety
Individual ethic
Beneficence
Non maleficence
Autonomy
Justice
RTCs do not guarantee benefit May result in harm Allocate treatment by chance (justice) Place burdens and confer benefits Benefit future patients
Issues considered in an ethical trial
Clinical equipoise - reasonable uncertainty or ignorance about better treatment or intervention Scientifically robust Ethical recruitment Valid consent Voluntariness and right to withdraw
Therefore approval from an ethics committee
Scientifically robust
- addresses relevant or important issue
- ask valid questions
- appropriate study design and protocol
- ability to find clinically important effect
- acceptable risks compared to anticipated benefits
- justify use of placebo
- provisions for monitoring the safety and well being of patients
- provisions for appropriate reporting and publication
Ethical recruitment
Do not use:
- Participants from communities that are not likely to benefit e.g. cannot test AIDs drug trials in developing world countries
- inappropriate use of participants with high risk of harm compared to benefits e.g. pregnant ladies
- participants likely to be excluded form analysis
Do not exclude:
- people who differ from homogenous group e.g. non white people
- people who are difficult to get valid consent from e.g. mentally ill
Valid consent
Knowledgable informant Appropriate information - verbal and written - thinking period - right for withdrawal
Participant:
Informed
Competent decision maker
Legitimate authoriser
Signed consent form as evidence for valid consent
Voluntariness
Needed for consent to be valid
Free from manipulation or coercion
Research committee
Research governance - design and conduct of study - recruitment of participants - care and protection of participants - confidentiality - informed consent - community considerations Financial management Resource implications
Insure dignity, rights, safety and well being of participants is adhered to primarily
