Therapeutic Investigations

There are three key questions to be answered during drug development:

With few exceptions, none of these is easy to answer definitively within the confines of a preregistration clinical trials programme. Effectiveness and safety have to be balanced against each other. What may be regarded as 'safe' for a new oncology drug in advanced lung cancer would not be so regarded in the treatment of childhood eczema. The use of the term 'dose', without explanation, is irrational as it implies a single dose for all patients. Pharmaceutical companies cannot be expected to produce a large array of different doses for each medicine, but the maxim to use the smallest effective dose that results in the desired effect holds true. Some drugs require titration, others have a wide safety margin so that one 'high' dose may achieve optimal effectiveness with acceptable safety.

14 Medicines need instruction manuals just as do domestic appliances.

There are two classes of endpoint or outcome of a therapeutic investigation.

• the therapeutic effect itself e.g. sleep, eradication of infection

• a surrogate effect, a short-term effect that can be reliably correlated with long-term therapeutic benefit e.g. blood lipids or glucose or blood pressure.

A surrogate endpoint might also be a pharmacokinetic parameter, if it is indicative of the therapeutic effect, e.g. plasma concentration of an anti-epilepsy drug.

Use of surrogate effects presupposes that the disease process is fully understood. They are employed (when they can be justified) in diseases for which the true therapeutic effect can be measured only by studying large numbers of patients over years. Such long-term outcome studies are indeed always preferable but may be impracticable on organisational, financial and sometimes ethical grounds prior to releasing new drugs for general prescription. It is in areas such as these that the techniques of large-scale surveillance for efficacy, as well as for safety, under conditions of ordinary use (below), would be needed to supplement the necessarily smaller and shorter formal therapeutic trials employing surrogate effects.

Surrogate endpoints are of particular value in early drug development to select candidate drugs from a range of agents. Over-zealous fixation on the use of surrogate endpoints can, however, lead to serious errors in decision-making.

Therapeutic evaluation

The aims of therapeutic evaluation are three-fold.

• To assess the efficacy, safety and quality of new drugs to meet unmet clinical needs.

• To expand the indications for the use of current drugs (or generic drugs15) in clinical and marketing terms.

• To protect public health over the lifetime of a given drug.

15 A drug for which the original patent has expired, so that anyone may market it in competition with the inventor. The term 'generic' has, however, come to be synonymous with the nonproprietary or approved name (see Chapter 6).

TABLE 4.1 Process of therapeutic evaluation


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