Clinical trials defining effects

Monthly aerosolized pentamidine has been utilized as prophylactic therapy against Pneumocystis carinii pneumonia in high-risk patients with HIV infection. While effective, this therapy fails in a certain percentage of patients. In the large clinical trials defining the clinical efficacy of this mode of therapy, the dose-response curve was not determined. Whether patients who failed prophylaxis did so because of inadequate deposition of aerosolized pentamidine or other unknown factors remained uncertain. Figure 13 represents summary data from a smdy in 58 patients receiving directly supervised monthly therapy in... 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

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 beneht ratio, i.e. the benefits should outweigh any associated risk. A drug is rarely 100 per cent 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/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 per cent of all patients. If the observed incidence is below the minimal acceptable level, then clinical trials are normally terminated. 

Clinical trials are divided into four phases. These are Phase I to Phase IV (Fig. 6.1). These trials are conducted with specihc purposes to evaluate the safety and effectiveness of the drug in defined population groups. A recent proposal is to conduct Phase 0 —a microdosing trial on subjects. Exhibit 6.4 provides more details on this new topic. 

The EU Clinical Trials Directive contains specific provisions regarding the conduct of clinical trials, including multicentre trials, on human subjects. It defines clinical trial as any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to... 

---