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or possibly even taken off the market when our knowledge base on the product changes. I do not think a drug withdrawal should be looked at as a criticism of the FDA, but a realization that our knowledge continues to evolve. Unfortunately, I have read the transcripts of congressional committees led by inquisitors who severely criticize regulators when adversity is later discovered from an agent that was approved on quite a meritorious application. If we can get the ground rules straight and understand that our knowledge base evolves and that we might have to take a different regulatory decision-making course as this knowledge advances, then we can accept the earlier approval without faulting our regulatory colleagues. This approach is needed if we are to fundamentally change for the better the drug development process. This is a difficult change since so much of the process is developed by lawyers who look upon the process as a litigation, with guilt or innocence to be determined, instead of by scientists who are continuously learning as more information is collected. |
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XII. Issues and Concepts in Drug Development |
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The field of drug development is vast and often specific to a given compound and the indications sought for its use. No chapter can provide an ABC guide to development. What is often a surprise is that development is applied in a general manner without a clear understanding of the market needs, without careful preclinical testing of the drug's effectiveness and especially its comparative effects to other available agents. In the remaining portions of this chapter, I am going to direct my thoughts to cardiovascular drug development; I believe that the discussion could be generalized to other areas of drug development as well. |
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When one is considering developing an antiarrhythmic, there is a need to go beyond the antiarrhythmic label. Are we discussing a drug aimed at the treatment of supraventricular arrhythmias or are we discussing a drug that will be used for the treatment of ventricular arrhythmias? Are we talking about arrhythmia prevention, acute conversion, or a long-term prophylaxis? What is the drug's mechanism of action? What is available for therapy alternatives? A sodium channel blocker needs to have a specific attribute: perhaps less toxicity; perhaps less proarrhythmia. One has to ask if animal studies unambiguously show the advantages of the drug, warranting the program to go forward. Some of these issues appear obvious, but some of the considerations are often not addressed in the preliminary stages of drug development. When the class I sodium channel blockers were made suspect after the CAST study, the rush was on to find and develop type-III amiodarone-like agents. However, there was no evidence that a pure type-III drug was superior to a mixed function |
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