Lec 3&4 Clinical Trials Flashcards
Define 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
Purpose of a clinical trial
To provide evidence of treatment efficacy and safety
Efficacy- ability of a health care intervention to improve the health of a DEFINED GROUP under SPECIFIC CONDITIONS
SAFETY - the ability of a health care intervention not to harm a DEFINED GROUP under SPECIFIC CONDITIONS
In order for a clinical trial to give a fair comparison of effect and safety it must be what?
Reproducible
Controlled
Fair
What are the stages of drug development and monitoring?
Pre- clinical phase(lab studies) - pharmacology/ animal toxicology, cell cultures/ animals
Phase 1 (volunteer studies) - pharmacodynamics/ pharmacokinetics/ major side-effects, <100 healthy volunteers
Phase 2 (treatment studies) - effects and dosages/ common side effects, <1000 patients
Phase 3 (clinical trials) - comparison with standard treatments, <10000 patients
Phase 4 (post-marketing surveillance) - monitoring for adverse reactions/ potential new users, whole population
What are non-randomised clinical trials and what are the disadvantages?
AllocTion of patients receiving a new treatment to compare with a group of patients receiving the standard treatment
- allocation bias (patient/ clinician/ investigator)
- confounding (known and unknown)
What is comparison with historical controls and what are the disadvantages?
Comparison of group patients who had standard treatment with. Group receiving new treatment
- selection often less well defined
- treated differently from new treatment group
- less info about potential bias/ confounders
- unable to control confounders
Steps involved in a randomised controlled trial
Define: disease of interest/ patients eligible/ patients excluded/ treatments to be compared/ outcomes to be measured/ possible bias and confounders
Conduct of the trial: identify a source of eligible patients, invite to trial, consent, allocate fairly to treatments, follow up identically, minimise losses, maximise adherence to treatments
Comparison of outcomes: observed difference, arisen by chance (statistically significant), how big is the difference (clinically important), is difference attributable to treatments (design and conduct good)
Reasons for pre-defining outcomes
Define what/ when/ how outcomes measured before start of clinical trial
- prevent data dredging/ repeated analyses
- protocol for data collection
- agreed criteria for measurement and assessment of outcomes
Compare primary and secondary outcomes
Primary:
Preferably only one, used in the sample size calculation
Secondary: other outcomes of interest, often includes occurrence of side-effects
Types of outcomes
Patho-physiological e.g. tumour size, thyroxine level, ECG changes
Clinically defined e.g. mortality, morbidity, disability
Patient- focussed e.g. quality of life, psychological well-being, social well-being, satisfaction
Features of an ideal outcome
Appropriate and relevant - to patient/ clinician/ society
Valid and attributable - any observed effect can be reasonably linked to treatments being observed
Sensitive and specific - chosen method of measurement can detect changes accurately
Reliable and robust - outcome measurable by different ppl in various settings -> similar result
Simple and sustainable - method of measurement easily carried out repeatedly
Cheap and timely - not excessively expensive to measure nor has a long lag time
Timing of measurements
Baseline measurement of relevant factors (inadvertent differences in groups)
Monitoring outcomes during trial (possible/ adverse effects)
Final measurement of outcomes
What is non-random allocation?
Allocation of participants to treatments by a
Person, historical basis, geographical location, convenience, numerical order etc.
Leads to a potential for allocation (selection) bias and confounding factors go unwittingly cause unidentified differences between the treatment groups
What is random allocation And what are the benefits?
Allocate participants to the treatments fairly
E.g. random number tables, computer generated random number allocator
- minimal allocation bias
- minimal confounding (likely similar size and characteristics by chance)
Benefits of blinding
Prevents:
- behaviour effect (patient May alter behaviour/ expect an outcome)
- non- treatment effect (clinician alter behaviour/ care/ interest in patient)
- measurement bias (alter approach)
Single/ double/ triple blind
Single blind - one of patient/ clinician/ assessor doesn’t know treatment allocation
Double blind - 2 of patient/ clinician/ assessor doesn’t know treatment allocation
Triple blind - all don’t know allocation
When might blinding be difficult?
Surgical procedures
Psychotherapy vs anti-depressant
Alternative medicine E.g. acupuncture vs western e.g. drugs
Lifestyle interventions
Prevention programmes
Define the placebo effect
Even if therapy irrelevant to patients condition the patients attitude to illness and the illness may improve by a feeling something is being done
Define placebo
Insert substance made to appear identical to active formulation with which it is compared
(Only when no standard treatment available) form of deception, need told may receive
2 types of losses to follow-up and how to prevent
Appropriate - clinical condition
Unfortunate - choose to withdraw
- practical follow up and minimise Inconvenience - honest about commitment - avoid coercion - maintain contact
What is explanatory ‘as treated’ analysis?
Anylses only those who complete follow-up and complied
Compares physiological effects
Loses effects randomisation
Non-compilers likely systematically different (selection bias and confounding)
Gives larger sizes of effect
What is pragmatic trial or intention to treat analysis?
Analyses according to original allocation to treatment groups (regardless follow up or compliance)
Compared likely effects in routine clinical practice
Preserved randomisation
Smaller and more realises sizes of effect
What is the declaration of Helsinki and international code of medical ethics?
The health of my patient will be my first consideration
A physician shall act only in the patients interest when providing medical care
Collective vs individual ethics
Collective - all patients should have treatments properly tested for efficacy and safety
Randomised clinical trials aim properly test treatments efficacy/ safety
Individual - principle of beneficence/ non-Maleficence/ autonomy/ justice
RCTs do not guarantee benefit/ may cause harm/ treatment by chance/ burdens and confer benefits (for the benefit of future patients)
Issues to consider for a clinical trial to be ethical
- clinical equipoise (reasonable uncertainty/ genuine ignorance about better treatment/ intervention)
- scientifically robust (relevant/ important issue, valid question, appropriate study design/ protocol, potential to reach sound conclusion, justify use of placebo, acceptable risks, monitoring safety provisions, arrangements appropriate reporting/ publication)
- ethical recruitment (communities likely benefit, low risk of harm compared benefits, included in analysis, people who differ ideal homogenous group, ppl difficult to gain valid consent from)
- valid consent (knowledgeable informant, appropriate information, competent decision maker, legitimate authoriser)
- voluntariness (pre requisite for consent, decision free (perceived) coercion/ manipulation)
Approval by research ethics committee
What do reasearch ethics committees focus on?
Scientific design and conduct of study
Recruitment of research participants
Care and protection of research participants
Protection of confidentiality
I formed consent process
Community considerations
