randomised controlled trials Flashcards
scientific medicine:
* Differs from other sorts of medicine by being based on evaluation of — for –
* One important function of — is to allocate patients to the — that
will benefit them most
* To do this, we need a way of evaluating treatments that is
– –
– –
– —
evidence
effective treatment
diagnosis
treatment
replicable
public
peer reviewd
preclinical studies:
* On average, 1 in 5,000 drug compounds enter —
– Following high through-put – of many compounds e.g. for –
* Preliminary assessment of – and —
– First assessment of a safe dose to be used in subsequent human trials
* May incorporate a combination of in silico (e.g.—-target simulations), in
vitro and in vivo (—) studies
preclinical research
screening
stability
pharmacology and toxicity
drug
animal
phase 0 trial :
* Also called a — trial or “proof-of —- ” trial
– A relatively new phase, used in a few therapeutic areas (e.g. — )
Aim
* Initial evaluation of — . — effect is not assessed.
– Provide —- regarding what the drug does to the body and what the
body does to the drug
– i.e. Does the drug behave as expected in humans?
Conduct
* – duration with a— number of volunteers (<—)
* – doses found to be non-toxic in the animal studies are often used
– “micro-dosing”, sub-therapeutic doses
pre phase 1 trial and proof of concept
oncology
pharmacokinetics
therapeutic effect
preliminary data
short
small
<15
low doses
phase 1:
Aim
* Assessment of clinical — and —
– Determine if the drug can — be given to humans, and what — levels can be given without causing serious side effects.
Conduct
* Usually conducted on — volunteers
* May involve anything from – to – participants
* Drug — and — assessed
* – doses may be assessed
If drug proves safe in healthy volunteers, phase 1 trials may next proceed in patients
pharmacology ad toxivity
safely
dosage
healthy
20-100
metabolism and bioavalibiltiy
multiple
phase 2 trial :
Aim
* Initial clinical investigation for treatment — ( – )
Conduct
* – number (— ) of closely-monitored patients receive the drug
* – and — also evaluated
* Phase 2a trials
– Usually – studies designed to demonstrate clinical – or biological –
* Phase 2b trials
– Determine the – (—) dose at which the drug shows biological – with minimal — (‘definitive — studies)
effect ( efficacy )
small ( 50-300)
close
safety and effectiveness
pilot studies
efficiency , activity
optimal ( therapeutic ) dose
biological activity
minimal side effect
dose finding studies
phase 3 :
Aim
* – assessment of — .
– The safety profile of the new drug remains –
Conduct
* Often – trials in a – patient groups (300–3,000 or more depending
upon the disease/medical condition studied)
– — duration than other phases
* Usually the drug is compared with current ‘ – standard’ treatment
– Controlled — of treatment
* Common that regulatory approval is given, based on initial data, while the trial is ongoing
definitive
efficacy
limited
multicenter
large
long
gold
controlled evaluation
phase 4 trials:
* Also called postmarketing — studies
– so they are not an actually “ — trials”
Aim
* To determine long term – and –
– May refine prescribing indications by documenting – complications, subgroups of patients with poor response
Conduct
* Surveillance of anyone obtaining treatment with the new therapy by a physician
* Monitoring of adverse reactions and long-term consequences of use of the drug
* Might include clinical data from > 10,000 patients
surveillance
clinical
long term safety an effectiveness
rare
importance of clinical trials:
* The decision about the value of a new — , — drug, — or medical – will rest on the clinical trials
* Vital that these are conducted so that the possibility of – is minimised
– Key features (discussed later) aid in minimising –
three key elements of a treatment trial is a trial:
* of a defined —
* in a defined —
* against a defined ( – ) endpoint
- main considerations when conducting a clinical trial is — and —
interventions , therapeutic drugs , vaccines , medical device
bias
bias
treatment
patient group
primary
patient safety and trial validity
4 ket methodological features:
* —
– The treatment is evaluated against a defined alternative
* —
– Patients are allocated to treatments at random, ensuring
comparability
* —
– To reduce bias
* — analysis
– Analysis based on treatment allocation, not adjusted for
compliance
controlled
randomised
blinded
intention to treat
feature: control
* The control group
– Used as a — for —
– Allows clear — of results
– Control group receives (as close as
possible) the same treatment as the
intervention group except for the
intervention being assessed
– Compensates for the Hawthorn
effect and for the unusual intensity
of treatment during trials
- choice of control groups:
* Type of control treatment may be any of
1) —
2) – treatment
3) different – or – of the study treatment
4) a different – treatment.
* Some trials use more than one control group
* What makes a good placebo?
– – and — (allows— )
– Often needs to be – for a particular trial
baseline for comparison
interpretation
placebo
n0
different dose or regimen
active
inert and indistugnishble
blidning
tailored
feature : randomised:
* Random allocation of patients to treatments
* No characteristic of the patient can—
the treatment they receive
* Ensures— of treatment and control
groups
* But does not allow for patient—
– Which may be important in determining treatment success
feature: blidning
* Types
– No blinding ( —label)
– single (either subjects or assessors blind)
– double (both subjects or assessors blind
– triple (so is —)
* Eliminates–
influence
comparability
preference
open label
data analyst
bias
why not an open label trial:
* Open-label trials
– Participants are— which treatment they have been allocated to (unblinded)
– But it may be possible to blind the assessment component of the trial and randomisation may also be possible
* Uses of open-label trials
– When it is not — to blind treatments e.g. –
* Potential for — and/or —
– When there may not be a – treatment to compare against
* so the trial has just one treatment
– When blinding would be —
* A significant placebo effect or Hawthorn effect is anticipated
aware
not feasible
surgery
section ot observer bias
control
ineffective
feature : intention to treat analysis
* All persons randomized to a treatment are
counted in the analysis
– Not just those who complete it or comply with it
* This means we are evaluating the treatment –
* Useful if treatments are long
* Analyzing those who completed treatment as
required is called the — analysis
- ethical issue - equipoise:
* Equipoise: there must be genuine — as to whether the new treatment is
better or not
– But, of course, there should be no grounds for believing it increases risk of harm
policy
per-protocol
uncertainty
ethical issue: consent
* Patients may receive treatment
which turns out to be inferior, or may
simply get a placebo
* They will have to forego their right to
know their treatment
* For these reasons, informed consent
is vital
ethical issue: reduced capacity
* Some patients will have reduced capacity to understand the issues or to
give consent
* Their interests require special —
ethical issues : fair distribution of benefit
* The people in the trial must stand to benefit – not necessarily as
individuals but at least as a group
– Altruism : doing things for the good of others, is a right
* Doing research on captive populations or groups who are unlikely to
benefit is unethical
protection
- Clinically significant: The treatment must produce a — effect in terms of the patient’s health – a drug that lowers cholesterol by 2% is no actual use!
- Statistically significant: The treatment benefit must have been so – that it is unlikely to have occurred by — in a patient group as big as the one being
studied. - – is the degree to which a piece of research actually tests the research question it sets out to answer
- Internal validity is the goodness of the – of the research
– Good – features
– Adequate measures to control bias? - External validity is the degree to which the research relates to–
worthwhile
large
by chance
validity
design
methodological
clinical practice
factors affecting external validity:
* — of trial methods
– Choice of control treatment, assessment, outcome measures
* generelizibility across –
– Health care system factors (country differences)
– Service resource available (e.g. was trial conducted in centres of excellence?)
* Generalizability across –
– Eligibility criteria e.g. exclusion of patients with comorbidities. Highly selected patients?
– CONSORT diagram and description of baseline characteristics are important
* — often neglected in reporting of trials
* – trials (which measure effectiveness rather than efficacy) are not common
appropriatness
situtations
people
external validity
pragmatic
limitations of RCT:
* Good for evaluating pharmaceutical—
* Less good for interventions which require– training (eg. surgery,
psychotherapy)
– Need to randomize—, not patients
* Hard to — trials of complex interventions
– e.g. multidisciplinary team interventions
– Cluster – trials may be better a option in these scenarios
– e.g. sequential randomization of hospitals to a new surgical training program
intervention
operator
randomised operators
conduct
randomised trials
interpreting negative trials:
* If the trial didn’t show a treatment
effect, could this be because it
wasn’t big enough to have a
reasonable chance of finding one?
– The smaller the trial, the –
chance it has of showing a
treatment effect, even if one is
there
– The smaller the treatment
effect that would be of practical
importance, the — the trial
you need to catch it
- navigating the clinical trial literature:
* No single trial can evaluate a treatment fully
* Each trial will be particular in
– Choice of dose etc.
– Choice of patient eligibility
– Choice of endpoint
– Choice of comparison (control)
* Systematic reviews provide a broad picture
less
bigger
PICO : used to help formulate well defined searchable question for research objectives:
P: patinet population or problems as characteristics , status
I: intervention/ exposure , is it medical surgical etc
C: comparison : gold standard?
O: outcomes
clinical trial failure:
* 90% of new therapeutic products that reach
clinical testing are subsequently not
approved or reach commercialization
* Just over half (52%) due to lack of efficacy
– The treatment doesn’t work (in the proposed
dosage or formulation)
* A quarter (24%) due to safety issues
– adverse drug reactions
* Quite surprisingly, a quarter (24%) fail due to
various technical or commercial reason
question:
If certain types of people do not agree to participate in a clinical trial,
then this may influence which one of the following?
1) Blinding
2) Clinical equipoise
3) External validity
4) Fair distribution of benefit
5) Internal validity
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