Clinical Pharmacology and Therapeutics
A Textbook of Clinical Pharmacology and ... - clinicalevidence
A Textbook of Clinical Pharmacology and ... - clinicalevidence
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CLINICAL DRUG DEVELOPMENT 89<br />
Too many statistical<br />
comparisons performed<br />
differences should be reported as confidence intervals (usually<br />
95% confidence intervals). Such intervals will diminish as<br />
the sample size is increased. Confidence intervals reflect the<br />
effects of sampling variability on the precision of a procedure,<br />
<strong>and</strong> it is important to quote them when a ‘non-significant’<br />
result is obtained, <strong>and</strong> when comparing different estimates of<br />
effectiveness (e.g. drug A in one trial may have performed<br />
twice as well as placebo, whereas drug B in another trial may<br />
have performed only 1.5 times as well as placebo; whether<br />
drug A is probably superior to drug B will be apparent from<br />
inspection of the two sets of confidence intervals).<br />
If many parameters are analysed, some apparently ‘significant’<br />
differences will be identified by chance. For example, if<br />
100 parameters are analysed in a comparison of two treatments,<br />
one would expect to see a ‘significant’ difference in<br />
approximately five of those parameters. It is therefore very<br />
important to prespecify the primary trial end-point <strong>and</strong> secondary<br />
end-points that will be analysed. Statistical corrections<br />
can be applied to allow for the number of comparisons made.<br />
One must also consider the clinical importance of any statistically<br />
significant result. For example, a drug may cause a statistically<br />
significant decrease in blood pressure in a study, but if<br />
it is only 0.2 mmHg it is not of any clinical relevance.<br />
CLINICAL DRUG DEVELOPMENT<br />
For most new drugs, the development process – following a<br />
satisfactory preclinical safety evaluation – proceeds through<br />
four distinct phases. These are summarized below. Figure 15.3<br />
illustrates the overall decision-making process for determining<br />
whether or not a new therapy will be clinically useful.<br />
PHASE I<br />
TYPE I ERROR<br />
False-positive result<br />
(significant difference found<br />
when no difference present)<br />
Too small sample size<br />
(insufficient power)<br />
Figure 15.2: Different types of statistical error.<br />
TYPE II ERROR<br />
False-negative result<br />
(no significant difference found<br />
when difference present)<br />
The initial studies of drugs in humans usually involve healthy<br />
male volunteers unless toxicity is predictable (e.g. cytotoxic<br />
agents, murine monoclonal antibodies). The first dose to be<br />
administered to humans is usually a fraction of the dose that<br />
produced any effect in the most sensitive animal species<br />
tested. Subjective adverse events, clinical signs, haematology,<br />
biochemistry, urinalysis <strong>and</strong> electrocardiography are used to<br />
assess tolerability. Depending on the preclinical data, further,<br />
more specific evaluations may be appropriate. The studies are<br />
placebo controlled to reduce the influence of environment <strong>and</strong><br />
normal variability. If the dose is well tolerated, a higher dose<br />
will be administered either to a different subject in a parallel<br />
design, or to the same group in an incremented crossover<br />
design.<br />
This process is repeated until some predefined end-point<br />
such as a particular plasma concentration, a pharmacodynamic<br />
effect or maximum tolerated dose is reached. Data from<br />
the single-dose study will determine appropriate doses <strong>and</strong><br />
dose intervals for subsequent multiple-dose studies. If the<br />
drug is administered by mouth, a food interaction study<br />
should be conducted before multiple-dose studies.<br />
The multiple-dose study provides further opportunity for<br />
pharmacodynamic assessments, which may demonstrate a<br />
desired pharmacological effect <strong>and</strong> are often crucial for the<br />
selection of doses for phase II. Having established the dose<br />
range that is well tolerated by healthy subjects, <strong>and</strong> in some<br />
cases identified doses that produce the desired pharmacological<br />
effect, the phase II studies are initiated.<br />
Key points<br />
Phase I studies:<br />
• initial exposure of humans to investigational drug;<br />
• assessment of tolerance, pharmacokinetics <strong>and</strong><br />
pharmacodynamics in healthy subjects or patients;<br />
• usually healthy male volunteers;<br />
• usually single site;<br />
• 40–100 subjects in total.<br />
PHASE II<br />
Phase II studies are usually conducted in a small number of<br />
patients by specialists in the appropriate area to explore efficacy,<br />
tolerance <strong>and</strong> the dose–response relationship. If it is ethical <strong>and</strong><br />
practicable, a double-blind design is used, employing either a<br />
placebo control or a st<strong>and</strong>ard reference drug therapy as control.<br />
These are the first studies in the target population, <strong>and</strong> it<br />
is possible that drug effects, including adverse drug reactions<br />
<strong>and</strong> pharmacokinetics, may be different to those observed in<br />
the healthy subjects. If the exploratory phase II studies are<br />
promising, larger phase III studies are instigated, using a<br />
dosage regimen defined on the basis of the phase II studies.<br />
Key points<br />
Phase II studies:<br />
• initial assessment of tolerance in ‘target’ population;<br />
• initial assessment of efficacy;<br />
• identification of doses for phase III studies;<br />
• well controlled with a narrowly defined patient<br />
population;<br />
• 100–300 patients in total;<br />
• usually double-blind, r<strong>and</strong>omized <strong>and</strong> controlled.<br />
PHASE III<br />
Phase III is the phase of large-scale formal clinical trials in which<br />
the efficacy <strong>and</strong> tolerability of the new drug is established.