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this situation, animal models will be especially important in terms of mortality trials in man with new agents similar to the ACE inhibitors, the A-II antagonists. |
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XVI. Integrating Technologies |
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Perhaps one of the most vexing questions in drug development relates to the often-observed problem of finding a field in evolution where the endpoints, diagnostic techniques, and methodologies are changing rapidly at times, making drug development part of the changing process. When I became interested in antiarrhythmic drug development, the technique of therapy selection employing programmed electrical stimulation was developing. The field was undergoing rapid change. Programmed electrical stimulation studies were not validated and, thus, using PES protection as an endpoint in drug development was a major leap of faith. Not to use the PES technique would have been remiss, but to solely utilize PES studies as an endpoint would have been a mistake for the development program. At that time, the appropriate role of PES was not defined clearly and different responses among the classes of drugs was also not known. Problems like this often appear in the preliminary stages of drug development. They can be even more problematic. While for antiarrhythmic drug development, PES studies still are utilized to demonstrate drug effect and in fact, not to expose a new antiarrhythmic to testing in the PES laboratory will raise serious regulatory questions. However, in the development of an antianginal agent, a similar evolution was occurring. Holter monitoring, identification of ischemia without chest pain, was being developed. A concept of silent ischemia was emerging. Using validating studies that employed techniques like the use of the nuclear vest was preceding, showing wall-motion abnormalities during silent ischemia, confirming that the EKG changes were not artifact or positional, but rather the ST depression without pain was true ischemia. In fact subsequent studies have found that when the episodes of silent ischemia are increased, the outcome to the patient is adverse and a reduction of silent-ischemic episodes correlates with an improved outcome. Other studies have not always found a correlation between overt anginal pain, its frequency, and silent ischemia. This is especially true in the diabetic population. The validation of the importance of silent ischemia endpoint was, and is, pretty good, especially in comparison to other endpoints often employed in drug development. However, utilizing silent-ischemia studies would not well serve the drug development program. The FDA does not recognize silent ischemia as an independent endpoint. The FDA grants no indication for the treatment of silent ischemia and maintains the singular primacy of the exercise anginal study for antianginal drug development. Indeed, there is no anti-ischemic drug development despite the widespread acceptance in the clinical cardiovascular specialists community of the importance of silent ischemia and |
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