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for cholesterol and perhaps studies are needed to validate the concept that lowering blood cholesterol to a target concentration will offer us the most benefit as compared to a fixed dose of a lipid-lowering agent. |
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XV. Methodologies and Drug Development |
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There is considerable importance to sequential drug development. The coordination of Phase-I studies, dose finding, key pivotal studies, and then drug interaction trials with followup of special populations and further patient exposures, is a basic tenant of drug development. Further dose evaluations and studies looking at combination with other known concomitant drugs that would be used are important to drug development. The advantage of parallel studies as opposed to crossover design trials can be argued. Utility of placebo-controlled trials, as well as the place of positive control studies, are all important aspects of the decisions that need to be made in the development program. Especially important is how are drugs to be assessed and what indices ought to be employed. This is, in part, a discussion of surrogate endpoints, partly a discussion of medical approaches to a problem, and partly a discussion of philosophy. Recently I was discussing with FDA the development of an IV antiarrhythmic for the most life-threatening of ventricular arrhythmias, especially patients undergoing a cardiac arrest who are unresponsive to electroshock therapy. The discussion of the relevant endpoint is most critical. Is the relevant endpoint arrhythmia termination, survival at one hour, at 24 hours, or survival at 3, 6, or 12 months? There are no answers to these questions, but there are intervening factors that affect our decision of endpoint selection in drug development. These patients are critically ill. If nothing can be done for them, they will rapidly die. If they live for a few more minutes with the arrhythmia terminated, there is maybe enough time to utilize an assist device. If they live longer and stabilize, some will do well but most will be scheduled for a diagnostic procedure such as a cardiac catheterization with probable angioplasty to follow if a culprit coronary lesion is identified that can be technically approached. With all of the intervening therapies, the endpoints further out become a result of the initial intervention and the result also of the additional medical therapies provided. Thus the determination of outcome must be related to the intervention. In this case, the administration of the study antiarrhythmic agentnot a host of other procedures that will be performedneeds to be assessed. Looking at all endpoints might be most appropriate and useful, but the critical benefit that the antiarrhythmic can offer us is termination of an arrhythmia that previously could not be terminated. |
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The determination of dose and endpoints is critical. The appropriate statistical powering of the number of patients to enter and the type of study is very important. The subtleties of the selection of endpoint and dose is critical |
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