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The indicator molecule serves to assess the state of health of the cultured cells. The dye, neutral red, is often used (healthy cells assimilate the dye, dead cells do not). The major drawback to such systems is that they do not reflect the complexities of living animals and, hence, may not accurately reflect likely results of whole-body toxicity studies. Regulatory authorities are (rightly) slow to allow replacement of animal-based test protocols until the replacement system has been shown to be reliable and is fully validated.
The exact range of pre-clinical tests that regulatory authorities suggest be undertaken for biopharmaceutical substances remains flexible. Generally, only a sub-group of the standard tests for chemical-based drugs are appropriate. Biopharmaceuticals pose several particular difficulties, especially in relation to pre-clinical toxicological assessment. These difficulties stem from several factors (some of which have already been mentioned), including:
THE DRUG DEVELOPMENT PROCESS 73
• the species specificity exhibited by some biopharmaceuticals, e.g. growth hormone as well as several cytokines, means that the biological activity they induce in man is not mirrored in test animals;
• for biopharmaceuticals, greater batch-to-batch variability exists compared to equivalent chemical-based products;
• induction of an immunological response is likely during long-term toxicological studies;
• lack of appropriate analytical methodologies in some cases.
In addition, tests for mutagenicity and carcinogenicity are probably not required for most biopharmaceutical substances. The regulatory guidelines and industrial practices relating to biopharmaceutical pre-clinical trials thus remain in an evolutionary mode.
Clinical trials serve to assess the safety and efficacy of any potential new therapeutic ‘intervention’ in its intended target species. In our context, an intervention represents the use of a new biopharmaceutical. Examples of other interventions could be, for example, a new surgical procedure, or a novel medical device. While veterinary clinical trials are based upon the same principles, this discussion is restricted to investigations in humans. Clinical trials are also prospective rather than retrospective in nature, i.e. participants receiving the intervention are followed forward with time.
Clinical trials may be divided into three consecutive phases (Table 2.5). During phase I trials, the drug is normally administered to a small group of healthy volunteers. The aims of these studies are largely to establish:
• the pharmacological properties of the drug in humans (including pharmacokinetic and pharmacodynamic considerations);
• the toxicological properties of the drug in humans (with establishment of the maximally tolerated dose, MTD);
• 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 or alleviate).
Table 2.5. 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 Efficacy and safety testing in small number of patients 2
III Large scale efficacy and safety testing in substantial numbers 3
of patients (1000-3000)
IV Post-marketing safety surveillance undertaken for some drugs Several
that are administered over particularly long periods of time
(number of patients varies)
The design of phase II trials is influenced by the phase I results. Phase II studies typically last for anything up to 2 years, with anywhere between a few dozen and 100 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 trials, ‘safe’ and ‘effective’ are rarely used in the absolute sense. ‘Safe’ generally refers to a favourable risk:benefit ratio, i.e. the benefits should outweigh any associated risk. A drug is rarely 100% effective in all patients. Thus, an acceptable level of efficacy must be defined, ideally prior to trial commencement. Depending upon the trial context, ‘efficacy’ could be defined as prevention of death or prolonging of life by a specific time frame. It could also be defined as alleviation of disease symptoms or enhancement of the quality of life of sufferers (often difficult parameters to measure objectively). An acceptable incidence of efficacy should also be defined (particularly for phase II and III trials), e.g. the drug should be efficacious in, say, 25% of all patients. If the observed incidence is below the minimal acceptable level, clinical trials are normally terminated.