Clinical trials performing difficulties

Since heparin protected the animals from histamine toxicity in a dose-response, it was thought to be safe to use in human patients for clinical trial. Heparin had of course been used in cardiovascular disease in large doses for many years. It was believed that there would be safety as long as the dosage was kept within the half gram used in cardiovascular disease. Further, since heparin was bound by histamine in the animal studies, it was believed that it would not be free in the blood to cause bleeding difficulties. Lee-White tests were performed on many of the patients and confirmed this finding. 

A large proportion of the technology appraisals so far performed by NICE on pharmaceuticals have been on products recently introduced into the marketplace. This has created difficulties for manufacturers trying to answer the questions posed by the appraisal. For most compounds, at the time of launch it is very unlikely that outcome studies will have been completed that allow accurate cost effectiveness calculations to be performed. The emphasis in Phase III is on clinical efficacy and safety to satisfy the requirements of the regulatory authorities. In most cases, it is impossible (and probably imethical) to perform pragmatic studies on the general population imtil safety and efficacy have been satisfactorily demonstrated in a tightly defined trial population. 

A number of controlled cUnical trials have been performed to evaluate the efficacy of the benzodiazepine receptor antagonist flumazenil in HE patients. In a subset of these patients, improvements following flumazenil have been spectacular. However, enthusiasm for this approach has been tempered by the possible confounding effects of prior exposure of patients to pharmaceutical benzodiazepines (used as sedatives or as part of an endoscopic work-up in cirrhotic patients) and by the poor correlation between the clinical response and blood levels of benzodiazepines in these patients. Adding to these difficulties is the short half-life and lack of an oral formulation for flumazenil. 

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