Dose determination, clinical trials

In pharmaceutical and medical device development, clinical trials are classified into four main phases designated with Roman numerals 1,11, III and lY The various phases of development trials differ in purpose, length and number of subjects involved. Phase I trials are conducted to determine safe dose levels of a medication, treatment or product (National Institutes of Health, 2002). The main purpose is often to determine an acceptable single dosage - how much can be given without causing serious side-effects. Phase I trials will also involve studies of metabolism and bioavailabity (Pocock, 1983). The sample size of a Phase 1 clinical trial is usually small, ranging from 10-80 subjects (National Institutes of Health, 2002 Pocock, 1983). 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

GABAergic mechanisms. Animal studies suggest that ginkgo has anxiolytic effects that increase with advancing age. Despite evidence in several animal studies, there are few, if any, human studies that address its psychotherapeutic effects. Ginkgo remains to be tested in controlled clinical trials to determine in which disorders and at what doses it is effective. 

The application of the principles of dose-response relations to Phase II and III clinical trials focuses on the practical aspect of determining which doses will be selected for these trials and which will be taken forward to registration (see below). Each subject in a clinical trial will have his or her own efficacy and safety dose-response curve for a given drug. The shape and position of these curves will be determined by individual subject characteristics - age, gender, genetically... 

In Phase 2 the studies are conducted to prove the therapeutic concept and evaluate efficacy and assure that measures of efficacy are adequate. Importantly, dose-response studies are conducted to determine the therapeutically useful dose range and to establish doses to be used in full-scale clinical trials. These studies are closely monitored and well controlled in a small to moderate numbers of patients with the condition of interest. Study results may also give some idea of common dose-related adverse events following short-term therapy. 

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