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the validity of the Holter methodology to assess silent ischemia. In this field a marked dichotomy has developed with trials designed to test a monotherapy in terms of exercise time to angina compared to a clinical cardiology approach of combined therapy with the assessment of reversible ischemia regardless of whether it is silent or overt anginal pain. In cardiology, the goal is to reduce the ischemic burden first procedurally, if possible, and then to provide medical therapy when ischemia is still present at rest or on exercise. |
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Knowledge of the nuances of the given field, the intricacies that the development drug process must abide by, is so very crucial. After organizing a course on Cardiovascular Drug Development for 15 years, I can appreciate the complexity of the process and the need for familiarity with the issues. Not to take part intimately in this evaluative process and to casually walk onto the scene, review other development plans, and discuss some issues with clinicians in the field will doom a plan to excessive expense and often whole aspects of a development plan will be in a direction that will not be productive or could lead to outright failure. No wonder the costs of development are so high and the results so poor. |
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XVII. Decisions in Development |
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With the development program underway, a number of branch points often develop that require critical decisions. Establishing dose, blinding studies, organizing centers, and dealing with IRBs are all part of development vagaries. Especially vexing is a need for studies clearly demonstrating effect and the IRBs pressures to optimize patient care and the administration of potentially beneficial established therapies. Tension develops between these cross purposes and the clinical demands are often pressing. Compromise is often needed, but the team guiding the development program needs to resist some of these substantial pressures. Compromises that limit one's knowledge about the drug are to be avoided. Developers must be encouraged to be relentless and not easily compromise study integrity. This is because all too often the perceived requirement for therapy is based on little evidence. I can remember a leader in the heart failure field blocking a comparative evaluation of an ACE inhibitor without digitalis even though so many doubt the effectiveness of the digitalis glycosides. Another situation was with a vociferous investigator who pushed very hard to prevent a study of digitalis acutely withdrawn in CHF patients receiving ACE inhibitors. It was unethical not to use digitalis. But this is despite the known incidence of up to 60% of patients with the diagnosis of CHF who are not being treated with ACE inhibitors. The question arises: is it unethical to withdraw digitalis and administer ACE inhibitors in patients? |
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