5. Design of a Clinical Trial for a New (Analgesic) Drug Flashcards
Designs of clinical trials for new drugs
A clinical trial for a new agent is carried out during phase II or phase III of the drug’s
development
Phases of drug development
Preclinical development involves animal studies into aspects such as
safety, efficacy and mutagenicity.
Phase I involves small group studies of fewer than 100 healthy volunteers,
looking at pharmacokinetics, pharmacodynamics and adverse effects.
Phase II recruits larger numbers of patients,
typically 200–300, in which the findings of the phase I studies are refined.
Phase III involves still larger numbers of patients,
usually in the thousands, who are entered into definitive RCTs.
Phase IV occurs after the drug has been licensed for use, and involves post-marketing
surveillance of its effects in much greater numbers of individuals.)
Ethics committee approval
No clinical trial can proceed without the approval
of an appropriately constituted ethics committee,
which will include laypeople amongst its members.
The scrutiny of applications by these committees is increasingly rigorous,
and in essence each committee seeks to preserve the full protection of the rights of
every potential participant.
Individuals must receive full information about all
aspects of the trial before they consent,
and they must be free to withdraw at any
stage without compromising their future care.
Committees will examine particularly
intently any trial in which financial inducements are involved.
Trial design
: the best-designed clinical trials seek to answer a single simple question:
in the case, for example, of a novel painkiller,
whether this new analgesic is superior to established treatments.
It is essential to have a control in the study, which in this
instance would be an analgesic in clinical use that was of proven benefit.
Trial design
must therefore involve defining endpoints for efficacy, and must also ensure that data
relating to adverse effects are collected
The use of placebos in trials of analgesics is
considered to be unethical, and so the drugs in all limbs of the trial will be
pharmacologically active.
Subject selection:
that the groups are matched as far as possible.
Such matching should include age, gender, American Society of Anesthesiologists
(ASA) status and racial characteristics
If the drug is to be used for treatment of chronic pain, then the trial can be a
double-blind crossover trial (see the following) in which the patient can act as his
or her own control.
Sufficient time must elapse between administrations of the two
drugs to ensure that the first one the patient has received is no longer exerting
any effect.
Sample size:
conclusions of any trial can be erroneous.
type I error
The study can determine either that there is a difference between treatments when none exists,
type II
or it can determine that there is no difference between treatments
when a difference does in fact exist.
In other words, the power of a study is its ability to reveal a difference of a
particular size. The power calculation allows the investigator to determine the sample
size necessary to demonstrate this difference.
It is calculated from 1-β,
where β is the type II error.
Trials are usually designed with a power of 80% (β = 0.2) or better,
90% (β = 0.1). The investigators must also decide the magnitude of the difference
that is sought
Randomization:
randomization of patients to one or other limbs of the trial is intended to remove bias.
The bias may be unconscious or hidden
Simple methods such as tossing
a coin are valid, although it is more common to use computer-generated
randomization.
Blinding
: it is ideal for the trial to be double blind, so that neither the patient nor the
investigator knows to which group they have been assigned. This is of particular importance when the outcome data are subjective, as in a comparison of analgesic
drugs or techniques.
Data collection
: obvious considerations apply to the scrupulous collection of data.
Inherent variation can be avoided by minimizing the number of investigators
involved in the process
Statistical evaluation:
the appropriate statistical tests must be chosen for the question
that is being asked
The
investigators must also decide whether the data are continuous and normally distributed,
in which case a parametric test is appropriate
The evaluation of an
analgesic would almost certainly involve the use of visual analogue scales, about
which statisticians may disagree. Some argue that response to pain is a biological
variable with a normal distribution; others contend that the data are not normally
distributed and that non-parametric tests should be applied
Null hypothesis
assumption made at the start of any investigation that
there is no difference between the populations, treatments and samples that are being
compared
This is usually 0.05 (which means that there is a 5%
likelihood of the difference occurring purely due to chance).
Type I or α error
Type I or α error:
In this case the null hypothesis is wrongly rejected,
and a difference is found when there is none.
This is a false positive.
type I error is reduced by requiring a higher probability value (making P smaller),
by increasing the sample size, or both. By convention, a 5% probability of making
a type I error is accepted, and the confidence level is given by (1 α).
Type II or β error
Type II or β error: in this instance the null hypothesis is wrongly proved, and so
no difference is found when one does in fact exist
his is a false negative. Type II
errors are easier to avoid than type I, and their commonest cause is a sample size
that is too small
Power
Power: the ‘power’ of a study is the measure of its likelihood of detecting a difference
between groups if a difference really does exist.
Sensitivity
Sensitivity: this is a measure of how good is a clinical test at excluding false positives
and is defined by the proportion of positives that are correctly identified by the test.
It is determined by the proportion of patients who test positive in relation to the
numbers who actually are positive.
