Lecture 2- Clinical trials Flashcards
what is a clinical trial
- Involves testing a new treatment compared to standard treatment and measuring outcomes overtime
- Comparison
Purpose of a clinical trial
To provide reliable evidence of treatment efficacy and safety
- Efficacy= the ability of a health care intervention to improve the health of a defined group under specific conditions
- Safety= the ability of a heath care intervention not to harm a defined group under specific conditions
clinical trials need to be
- reproducible controlled and fair
Stages of drug development and monitoring
- 4 phases
- Clinical trials = phase 3
- Phase 4= whole population (post marketing surveillance)
- Monitoring for adverse events
Who should take part?
- Inclusion criteria
- Exclusion criteria
These criteria then relate to the generalisability of any findings we have
Considering outcomes measures for CTs
Reasons for pre-defining outcomes
- Need to define what when and how outcomes are to be measured before starting clinical trial
- Prevent data dredging, repeated analyses
- Have a clear protocol for data collection
- Agreed criteria for measurement and assessment of outcomes
Primary outcomes vs secondary outcomes
Types of outcome
Timing of measurement
Features of an ideal outcome
How can we demonstrate two groups are equivalent… for a fair trial
- Collect baseline data on characteristics we think may relates to both the condition and the outcomes we are investigating
- E.g. if doing a CVD study would be important to have an equal number of smokers in each arm of trial
Ethics of trials
- Trials of new drug may do no harm
- Should only conduct a trial if you are genuinely in clinical equipoise and don’t know what is best treatment for pts
- Patients/participants must understand what participation involves (inc. known and unknown risks)
order to be able to give a fair comparison of effect and safety, a clinical trial needs to be:
- Reproducible- in experimental conditions
- Controlled- comparison of intervention
- Fair- unbiased without confounding
Clinical trials are subject to ….. ……–> differences observed in small trials (less than 1,000) are more prone to chance)
random variation
Non-randomised clinical trials
- Involve the allocation of pts receiving a new treatment to compare with a group of pts receiving the standard treatment
- BUT
- Allocation bias- by pt, clinician or investigator
- Confounding- known and unknown
- Non random allocation
- Allocation of pts to treatments by a person, historical basis, geographical location, convenience, numerical order etc
- Confounding factors (e.g. starting health or ethnicity in two different areas e.g. Leicester and Bath) unwittingly cause unidentified differences between the treatment groups being compared
Comparison with historical controls
- Comparison with historical controls involves the comparison of a group of patients who had the standard treatment with a group patients receiving a new treatment
- BUT for standard treatment group:
- Selection often less well defined, less rigorous
- Treated diff from new treatment group
- There may be less info about potential bias/confounders
- Unable to control for confounders
Randomisation
Allocate participants to the treatments fairly
- Should use ‘concealed allocation’ i.e. no possibility of predicting allocation of next patient (randomisation should be prepared by someone who is not entering pt and should be done at a distance)
- Prevents: selection bias
- Ensures: that we have 2 similar groups to minimise confounding
what does randomisation ensure
How to we randomise
Knowing the treatment allocation (open-label)
Knowledge of which participants is receiving which treatment may bias the results of a clinical trial
- Pt may alter behaviour, other treatment or even expectation of outcome (behaviour effect)
- Clinician may alter their treatment, care and interest in the patient (non treatment effect)
- Investigator may alter their approach when making measurements and assessing outcomes (measurement bias)
Blinding
Follow up participants in identical ways. Removes allocation bias -by ensuring that randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial.
- Single blind- one of patient, clinician, assessor does not know the treatment allocation (usually pt)
- Double blind- two of pt, clinician, assessor does not know the treatment allocation 9usually pt and clinician/assessor)
examples of blinding
- aim to make trearment appear identical in every way
- use a designated pharmacy to label identical containers for the treamtent with coe numbers and to have code sheet detailing which code number corresponds to each treatment
where blinding is difficult
- surgery
- psychotherapy vs anti-depressants
- alternative medicine e.g. acupunture
- lifestyle interventions
- prevention programmes
Confounding
: a factor that is associated with the disease and the outcome of interest, and this association is separate to the relationship between the risk factor (or intervention) being investigated.
Bias
: a systematic distortion in allocation/ measurement etc
- May effect selection (then essentially is a confounder)
- May effect outcome measurement by:
- Patient
- Doctor/researcher
- Other forms of bias etc publication bias
Steps involved in a randomised control trial (RCT)
what is a placebo
a placebo is an inert substanc emade to appear identical in every way to the active formulation with whcih it is to be compared e.g. appearance, taste, texture etc
placebo effect
Aim of placebo?
Cancel out any placebo effect that may exist in the active treatment
Ethical implications of placebo
- Should only be used when no standard treatment is available
- Use of a placebo is a form of deception
- Therefore it is essential that participants in a placebo-controlled trial are informed that they may receive a placebo
Comparing with ‘no treatment’
The effect comparing a new treatment group with a group receiving no treatment is to leave one unsure as to whether any observed difference was due to the new treatment or to the fact the group was receiving care.
Losses to follow up
Not every participant remains in the trial
- Their clinical condition may necessitate their removal from the trial (appropriate)
- They may choose to withdraw from the trial (unfortunate)
Minimising losses to follow up
Non -compliance with treatments
How to maximise adherence
Differentiate between explanatory and pragmatic trials and be able to explain the meaning of the term intention to treat analysis
- explanatory trial: ‘as-treated’ analysis
- pragmatic trial: ‘intention to treat’ analyis
Efficacy study (RCT)-
Pragmatic trial (effectiveness)-
Efficacy study (RCT)- under ideal conditions
Pragmatic trial (effectiveness)- real world results e.g. poor adherence
Explanatory trial: As-treated analysis
As-treated analysis- you only analyse those who have adhered to treatment
- Only looks at those who completed follow up and complied with treatments
- Compares the physiological effects of the treatment
- BUT No longer fully randomised study
- Non compliers are likely to be systematically different from compliers –> selection bias and confounding
- Not real world effects
Pragmatic trial: Intention to treat (effectiveness)
if you are in the study you are analysed whether you adhere to treatments of not
- Analyses according to original allocation
- Compares the likely effect of using the treatments in routine clinical practice
- Preserves randomisation
difference in results of ‘as-treated’ vs ‘intention to treat’ studies
clinical trials should normally be analysed on an ‘intention to treat’ basis
ethical practice within clinical trials
- A system of moral values/ principles of conduct applied to research
*
‘Ethical practice requires that participants, at a min, be fully informed, free to volunteer without inducement, free to opt out without redress, and be fully protected in regard to safety to the limits of best practice’
clinical trials must have
approval from ethics committes
What is a research ethics committee?
A group of people who discuss applications to check that ethics issues have been identified and planned for appropriately.
There are difference RECs for diff types of studies?
à which ethics committee- NHS or Med school?
NHS Research Ethic Approvalà research involving the NHS e.g. patients or service users, relatives or carers of patients within the NHS or a Health and Social Care organisation you will need to apply through Integrated Research Application System (IRAS).
HRA Approval à Health Research Authority (HRA) was introduced in 2016 for managing approval for all project based research in the NHS. The HRA brings together the assessment f governance and legal compliance with the independent REC opinion provide through the UK Research Ethics Service. It replaces the need for local checks f legal compliance and related matters by each participating NHS organisation in England. Applications are made through the integrated research application system (IRAS). HRA approval is required for all project based research that involves NHS organisation in England.
You only need ethics approval from one REC- may need to get additional local permission
Ethical principles that should be applied in clinical trials
- Respect for persons autonomy- informed consent
- Ongoing process
- Must be written, dated and signed
- Must understand nature, significance, implications and rsik
- To respect peoples privacy
- Data protection
- anonymity
- To ensure confidentiality of the peoples information
- Social justice
- The potential benefits outweigh the risks of the study
- Not to cause undue physical or mental harm to the
- Subject- assess risk and benefit
what information is required for informed consent to be given
- What their participation involves
- Potential risk and benefits (don’t exaggerate potential benefit)
- What the research is about
- What data is being collected and what will be done with it
- Where it will be stored, who has access to it, how long it will be kept
