1. Clinical pharmacology and therapeutics: goal, problems.

Methods to carry

out clinical trials. Phases of clinical drug development.

Human experiments progress in a common sense manner that is conventionally

divided into four phases. These phases are divisions of convenience in what is a
continuous expanding process. It begins with a small number of subjects (healthy
subjects and volunteer patients) closely observed in laboratory settings, and
proceeds through hundreds of patients, to thousands before the drug is agreed to
be a medicine by a national or international regulatory authority. It is then
licensed for general prescribing (though this is by no means the end of the
evaluation). The process may be abandoned at any stage for a variety of
reasons, including poor tolerability or safety, inadequate efficacy and commercial
pressures. The phases are:
• Phase 1. Human pharmacology (20–50 subjects): in healthy volunteers or volunteer
patients, according to the class of drug and its safety n pharmacokinetics and
pharmacodynamics- where practicable, tolerability, safety, efficacy.
• Phase 2. Therapeutic exploration (50–300 subjects): pharmacokinetics and
pharmacodynamic dose ranging, in carefully controlled studies for efficacy and
safety,11 which may involve comparison with placebo.
• Phase 3. Therapeutic confirmation (randomised controlled trials; 250–1000
subjects): test for efficacy on a substantial scale; safety; comparison with existing
drugs.
• Phase 4. Therapeutic use (pharmacovigilance, postlicensing studies) (2000–10
000þ subjects): n surveillance for safety and efficacy: further formal therapeutic
trials, especially comparisons with other drugs, marketing studies and
pharmacoeconomic studies.
 Initial animal studies-
Generally, the following are undertaken:
Pharmacodynamics – to investigate the actions relating to the proposed therapeutic
use. In addition, there is a need to investigate potential undesirable
pharmacodynamic effects of the substance on physiological functions.
Pharmacokinetics – the study of the fate of the active substance and its
metabolites within the organism (absorption, distribution, metabolism and
excretion of these substances). The programme should be designed to allow
comparison and extrapolation between animal and human.
Toxicology – to reveal physiological and/or histopathological changes induced by the
drug, and to determine how these changes relate to dose.10 These involve:
• Acute toxicity: single-dose studies that allow qualitative and quantitative
assessment of toxic reactions.
• Chronic and subchronic toxicity: repeat-dose studies to characterise the
toxicological profile of a drug following repeated administration. This includes the
identification of potential target organs and exposure– response relationships,
and may include the potential for reversibility of effects.
Generally, it is desirable that tests be performed in two relevant species, based on
the pharmacokinetic profile, one a rodent and one a non-rodent.
Genotoxicity – to reveal the changes that a drug may cause in the genetic material of
individuals or cells. Mutagenic substances present a hazard to health because
exposure carries the risk of inducing germline mutation (with the possibility of
inherited disorders) and somatic mutations (including those leading to cancer).
. Carcinogenicity – to reveal carcinogenic effects. These studies are performed for
any medicinal product if its expected clinical use is prolonged (about 6 months),
either continuously or repeatedly.
Reproductive and developmental toxicity – these tests study effects on adult male or
female reproductive function, toxic and teratogenic effects at all stages of
development from conception to sexual maturity and latent effects, when the
medicinal product under investigation has been administered to the female during
pregnancy.

Types of trials-
This is the classical randomised controlled trial (RCT), the most secure method
for drawing a causal inference about the effects of treatments. Randomisation
attempts to control biases of various kinds when assessing the effects of
treatments. RCTs are employed at all phases of drug development. Fundamental
to any trial are:
• A hypothesis.
• The definition of the primary endpoint.
• The method of analysis.
• A protocol.
Other factors to consider when designing or critically appraising a trial are:
• The characteristics of the patients.
• The general applicability of the results.
• The size of the trial.
• The method of monitoring.
• The use of interim analyses.22
• The interpretation of subgroup comparisons.
The aims of a therapeutic trial, not all of which can be attempted at any one
occasion, are to decide:
• Whether a treatment is effective.
• The magnitude of that effect (compared with other remedies – or doses, or
placebo).
• The types of patients in whom it is effective.
• The best method of applying the treatment (how often, and in what dosage if it is a
drug).
• The disadvantages and dangers of the treatment.

Dose–response trials. Response in relation to the dose of a new investigational

drug may be explored in all phases of drug development. Dose–response trials
serve a number of objectives, of which the following are of particular importance:
• Confirmation of efficacy (hence a therapeutic trial).
• Investigation of the shape and location of the dose– response curve.
• The estimation of an appropriate starting dose.
• The identification of optimal strategies for individual dose adjustments.
• The determination of a maximal dose beyond which additional benefit is unlikely to
occur.