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The study prevailed and to this day is one of the best demonstrations of the utility of digitalis in patients with signs of pulmonary congestion (5). |
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There are many critical times in drug development that require a strong will and clear purpose to stay the course. The drug development program may come upon adversity in terms of adverse toxicity or lack of efficacy that may provoke serious questions about the continuation of the project. To fail to terminate a project appropriately may lead to needless expenditures and inappropriate liability. However, far too often programs are jettisoned prematurely when indeed the project needs further study. Premature cancellation of a study by a data-monitoring or safety board can be extremely adverse with the loss of further data collection that could show results quite different. If at all possible, a study should not be terminated based on a trend. The study should be pursued until statistical significance is found for the adverse endpoint. If additional precautions can be undertaken for patients' safety without study termination, this would be the recommended course to take. |
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An example of a trying period in development was the increased toxicity reported with the calcium channel blocker, bepridil. Since the drug prolonged the QT interval, it seemed appropriate not to administer the agent to patients with an already prolonged QT interval and with the most severe LV function. However this course would probably have limited the drug's prescribing and might have lead to the FDA placing a black box labeling with a statement that the drug might be unsafe for the population excluded or that it was possibly unsafe because the drug was not studied in this population. Because of these considerations, which were in opposition to the corporate plan for the drug, it was decided to expose the drug in the population that was previously excluded. With the change in the development strategy, the drug was exposed to patients with poor LV function and those with QT prolongation. With the randomization of the first patients, severe arrhythmias and death were experienced, whereas previously the safety record was pristine when the conservative entrance criteria were employed. Clearly, the suspicions of possible proarrhythmia were well founded in these high-risk patients. While development was continued and some of the studies were redirected, the change in strategy could well have lead to the termination of drug development. |
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A more limited indication can still lead to approval and appropriate drug availability while unselected drug exposure can lead to severe adversity and drug development termination. It is nice, in fact desirable, to develop a block-buster product, but more often than not, reality needs to set in. An agent may continue in development for a more limited group and this may be appropriate given the pharmacodynamic and kinetic considerations for a given agent. A drug will eventually find its rightful place in the market in any event and thus initial self-deception wins nothing in the long run for the company. |
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