The Drug development process - Pharmaceutical Biotechnology: Concepts and Aapplications - page 88

Table 4.4 The clinical trial process. A drug must satisfactorily complete each phase before it enters the
next phase. Note that the average duration listed here relates mainly to traditional chemical-based drugs.
For biopharmaceuticals, the cumulative duration of all clinical trials is, on average, under 4 years

Trial phase Evaluation undertaken (and usual number of patients) Average duration (years)

I Safety testing in healthy human volunteers (20-80) 1

II Effi cacy and safety testing in small number of patients (100-300) 2

III Large-scale effi cacy and safety testing in substantial numbers of

patients (1000-3000)

3

IV Post-marketing safety surveillance undertaken for some drugs that

are administered over particularly long periods of time (number of
patients varies)

Several

• the toxicological properties of the drug in humans (with establishment of the maximally toler-

ated dose);

• the appropriate route and frequency of administration of the drug to humans.

Thus, the emphasis of phase I trials largely remains upon assessing drug safety. If satisfactory
results are obtained during phase I studies, the drug then enters phase II trials. These studies aim
to assess both the safety and effectiveness of the drug when administered to volunteer patients (i.e.
persons suffering from the condition the drug claims to cure/alleviate).
The design of phase II trials is infl uenced by the phase I results. Phase II studies typically last
for anything up to 2 years, with anywhere between a few dozen and a hundred or more patients
participating, depending upon the trial size.
If the drug proves safe and effective, phase III trials are initiated. (In the context of clinical tri-
als, safe and effective are rarely used in the absolute sense. 'Safe' generally refers to a favourable
risk:benefi t ratio, i.e. the benefi ts should outweigh any associated risk. A drug is rarely 100 per
cent effective in all patients. Thus, an acceptable level of effi cacy must be defi ned, ideally prior
to trial commencement. Depending upon the trial context, 'effi cacy' could be defi ned as preven-
tion of death/prolonging of life by a specifi c time-frame. It could also be defi ned as alleviation
of disease symptoms or enhancement of the quality of life of sufferers (often diffi cult parameters
to measure objectively). An acceptable incidence of effi cacy should also be defi ned (particularly
for phase II and III trials), e.g. the drug should be effi cacious in, say, 25 per cent of all patients.
If the observed incidence is below the minimal acceptable level, then clinical trials are normally
terminated.
Phase III clinical trials are designed to assess the safety and effi cacy characteristics of a drug
in greater detail. Depending upon the trial size, usually hundreds if not thousands of patients are
recruited, and the trial may last for up to 3 years. These trials serve to assess the potential role of
the new drug in routine clinical practice; the phase III results will largely dictate whether or not
the prospective drug subsequently gains approval for general medical use.
Even if a product gains marketing approval (on average, 10-20 per cent of prospective drugs
that enter clinical trials are eventually commercialized), the regulatory authorities may demand
further post-marketing surveillance studies. These are often termed 'phase IV clinical trials'.
They aim to assess the long-term safety of a drug, particularly if the drug is administered to