Test of endurance

To get a drug to market is a long, hard road and many fall by the wayside. In the first of a series of papers, Ray Burnett, scientific adviser for Allergan, describes the initial processes through which a compound passes

Until the 1930s, potential new drugs were tested on a very small number of patients in a very open and haphazard fashion. Safety was not a primary concern of the drug manufacturers and it was inevitable that disasters would occur. The first major event of this kind to be widely publicised was the 'sulphanilamide affair' in the US in 1937, in which sulphanilamide, a synthetic antimicrobial compound, was dissolved in diethylene glycol (antifreeze), principally for administration to children. More than 100 deaths resulted, mainly in children, and this led directly to the creation of the US Food and Drugs Act of 1938, under which no new drug could be introduced into the US until the Food and Drugs Administration (FDA) was satisfied as to its safety.

However, governments in Europe were preparing for war at this time, and similar legislation was not forthcoming. It was not until the next major disaster, thalidomide in the 1960s, that an extensive worldwide review of regulatory controls over the development of new medicines took place. In the UK, this led to the Medicines Act of 1968, in which, among other legislation, the clinical drug development process was further defined. Today the clinical trials process is an extensive one, calling for a wide range of expertise and with tight governmental regulatory control at a number of stages.

Clinical trials or 'studies' – the two terms are used synonymously – are classified into Phases I–IV. Concurrent trials in different phases may overlap, especially if repeated in different groups of patients, but generally a sequential order is followed. Each phase requires a different approach to trial design.

Phase I trials are the first in man using a new investigational agent. (Strictly speaking, a compound is not a 'drug' at this stage since this term implies that a medicinal benefit has been demonstrated.) The initial dose in man is determined by the toxicity profile of the compound as seen in animal model studies. A conservative dose, not expected to give rise to any toxicity, is selected in the first group of subjects, and in the absence of toxicity the dose is escalated in sequential groups to determine the pharmacological profile of the compound and/or the dosage at which some toxicity becomes apparent.

first studies

The very first studies consist only of a single dose of the study compound; longer periods of administration take place in subsequent studies, their duration depending on the intended duration of treatment with the compound in later studies in patients. Very often a crossover design is employed, in which the subjects receive in random order both the study compound and a matching placebo at different times, and after a suitable interval.

Phase I studies are usually conducted in young healthy adult male volunteers, the most notable exceptions to this practice being studies of female hormone compounds, which would be carried out in females only, and anti-cancer drugs, which are carried out in volunteer patients with resistant cancer.

The main objective of Phase I studies (see table 1) is to evaluate the safety and tolerability of a potential new drug. They may or may not provide data on an effective dose: for instance, a compound with antihypertensive activity will probably lower blood pressure in normal subjects, but a potential antibiotic will have no effect on subjects who do not have an infection, and similarly a potential anti-inflammatory drug will not have a therapeutic effect in subjects not having rheumatic disease. Occasionally, a quite unforeseen effect observed in Phase I will lead to an equally unforeseen clinical application of a drug, as evidenced by the testimony of several male volunteers in initial studies of sildenafil (Viagra), a drug originally intended for use as an anti-anginal agent!

volunteer safety

The second major objective is to determine the pharmacokinetic and pharmaco-dynamic profiles of the compound in human subjects. The pharmacokinetics of a compound is the study of its absorption, distribution, metabolism, and excretion in a living being (ADME). Pharmacodynamics is the study of the biochemical and physiological effects of a compound and its mechanism of action. The key features of these investigations and their rationale are listed in table 2.

It must be emphasised that the primary focus in Phase I studies is on safety, especially the safety of the volunteer subjects. These studies take place in specialised units, manned by physicians and nurses trained in cardiopulmonary resuscitation, and having the appropriate equipment to deal with such emergencies. Serious toxicities are, fortunately, rare. Usually they are the result of an undisclosed or undiagnosed illness on the part of the volunteer, and in other instances a direct relationship to the investigational agent cannot be proven.

potential toxicities

Mention should be made of clinical pharmacological studies in special groups such as the elderly, children, and those having renal or hepatic impairment. These are often termed Phase IB studies. The characteristics of a potential drug may be quite different in such groups. In addition, when a new drug is expected to be widely used in combination with another, for example as in cancer chemotherapy, a drug-drug interaction study is also required. This is a complex trial in which the effect of each drug on the pharmacokinetics and pharmaco-dynamics of the other is evaluated to determine potentially toxic interactions, or interactions which attenuate or enhance the activity of one or both drugs.

Despite the focus on safety in Phase I, sufficient information on the potential toxicities of a compound must be elicited in order to make a decision whether to continue with the clinical development into the next phase of study. This will take place only if no toxicities giving cause for concern arise during these initial investigations, and the expected pharmacological activity is demonstrated.