clinical trials Flashcards
Define and describe the purpose of clinical trials
define: 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: to provide reliable evdence of treatment efficacy and safety
Consider who should participate in a clinical trial
inclusion criteria- age, sex, health status
exclusion criteria- elderly, immunocompromised, children, other disease
why pre define outcomes?
– prevent ‘data dredging’, ‘repeated analyses’
– have a clear protocol for data collection
– agreed criteria for measurement and assessment ofoutcomes
Describe how we demonstrate two (or more) groups are equivalent…for a fair trial
- collect baseline data eg. bmi/smoking/age/gender/class
Describe key ethical considerations in trial design and conduct
Trials of new drugs may do harm • should only conduct a trial if you are genuinely in ‘clinical equipoise’ and don’t know what is best treatment for patients.
• Patients/participants must understand what participation involves (including known and unknown risks)
Explain the disadvantages of non-randomised clinical trials
- Allocation bias – by patient, clinician or investigator
* Confounding – known and unknown
advantages of random allocation
• Minimal allocation bias – randomisation gives
each participant an equal chance of being
allocated to each of the treatments in the trial
• Minimal confounding – in the long run, randomisation leads to treatment groups that are
likely to be similar in size and characteristics by
chance
safety
the ability of a healthcare intervention not to harm health
Describe the ‘placebo effect’, what a ‘placebo’ is, and how a ‘placebo’ addresses the
‘placebo effect’
placebo- A placebo is an inert substance made to appear identical in every way to the active formulation with which it is to be compared
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”
Discuss how to deal with ‘losses to follow-up’
loss to follow up-
• Make the follow-up practical and minimise inconvenience
• Be honest about the commitment required from
participants
• Avoid coercion or inducements, but can
recompense participants for their time/trouble
• Maintain contact with participants
secondary outcome
– other outcomes of interest – often includes occurrence of side-effects
types outcomes
pathophysiological eg. tumout size
clinically defined eg. death/mortality
patient focused eg. quality of life
features of ideal outcome
appropriate, valid, sensitive and specific, reliable, simple and sustainable, cheap and timely
what is a non randomised clinical trial
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 is non random allocation
Allocation of participants to treatments by a person, historical basis, geographical location, convenience, numerical order
what is non random allocation
Allocation of participants to treatments by a person, historical basis, geographical location, convenience, numerical order
what are historial controls
the comparison of a group of patients who had the
standard treatment with a group of patients
receiving a new treatment
disadvantages of historial controls
- selection often less well defined, less rigorous
- unable to control for confounders
- treated differently from ‘new treatment’ group • there may be less information about potential bias/confounders
definition random allocation
Allocate participants to the treatments fairly
how does open label treatment allocation introduce bias
– Patient may alter their 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)
advantages of blinding
Remove allocation bias – by ensuring that
randomisation gives each participant an equal chance of being allocated to each of the treatments in the trial
when is blinding difficult
• Surgical procedures • Psychotherapy vs. anti-depressant • Alternative medicine, e.g. acupuncture, vs. Western medicine, e.g. drug • Lifestyle interventions • Prevention programmes
define 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.
define bias
systematic distortion in allocation/measurement
ethical considerations placebo
• A placebo should only be used when no
standard treatment is available
(‘Declaration of Helsinki’ 2013, paragraph 29)
• 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
why is there loss to follow up
– their clinical condition may necessitate their removal
from the trial (appropriate)
– they may choose to withdraw from the trial (unfortunate)
why are people non adherent
– they may have mis-understood the instructions
– they may not like taking their treatment
– they may think their treatment is not working
– they may prefer to take another treatment
– they can’t be bothered to take their treatment
how to minimise non adherence
• Simplify instructions
• Ask about adherence
• Ask about effects and side-effects
• Monitor adherence, e.g. tablet count, urine level,
blood level
• Understand it is never possible to achieve 100%
adherence
what is an explanatory trial
“as treated analysis”
• Analyses only those who completed follow-up
and adhered to treatments
disadvantages explanatory trial
• Compares the physiological effects of the treatments BUT loses effects of randomisation • Non-adherers are likely to be systematically
different from those adhering to treatment ⇒
selection bias and confounding
what is a pragmatic trial
“intention to treat analysis”
• Analyses according to the original allocation
to treatment groups (regardless of whether they completed follow-up or adhered to treatment)
pros pragmatic trial
• Compares the likely effects of using the
treatments in routine clinical practice ALSO preserves effects of randomisation →
minimal selection bias and confounding
compare pragmatic (intention to treat) and explanatory )as treated)
• ‘As-Treated’ analyses tend to give larger sizes
of effect
• ‘Intention-to-Treat’ analyses tend to give
smaller and more realistic sizes of effect
steps of RTC
- disease
- treatments
- elegible patients (inclusion criteria)
- exclusion criteria
- outcomes measured
- bias and confounderrs
