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The concept of comparison of the new drug with the accepted best available treatment is common to all medical research. The problem in oncology is that there is in general no consensus as to the best available therapy. In fact, in some cases the best may be supportive care with no exposure to cytotoxics at all. Even in tumor types where some consensus does exist (e.g., platinum plus an alkylator in ovarian cancer), there is considerable regional, national, or international variation, which makes design of large-scale international collaborative Phase III studies particularly difficult. |
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In view of the numbers of patients required for statistical validity in Phase III trials, it is unusual for them to be performed in single institutions (or even single countries). This compounds the problems of assessment of anticancer response as discussed previously, and necessitates the adoption of the most incontrovertible endpoints such as survival time as the primary objectives in oncology Phase III trials. |
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The rapid pace of change in oncology may lead to the best treatment at the start of Phase III being considered wholly inadequate by the time the results of the trial are mature. It is also particularly difficult from both a moral and practical standpoint to perform a placebo-controlled trial in cancer patients, as few such patients will accept the possibility of placebo therapy for a lethal condition. |
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VII. New Challenges for Drug Development in Oncology |
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The explosion of knowledge about the control of cell division, motility and death that is evident in modern cell and molecular biology must be integrated into the practice of cancer medicine. |
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It is almost inconceivable that useful new drugs will not result from this expansion of knowledge [27]. However, it is unlikely that the traditional drug development path described in this chapter will serve us efficiently in identifying drugs with novel (non-DNA) mechanisms of activity. The history of cytokine development (such as Interferon) should serve as a warning in this respect. I believe that the current system is too heavily dependent on toxicological endpoints, based on the hypothesis that you have to do some harm to do some good in treating cancer. If this were entirely true patients experiencing the worst toxicities should have the best outcomes, and this is patently not true to any practising oncologist. |
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New cytokines, signal transduction inhibitors, protein biosynthesis inhibitors, cell adhesion promoters, and antimetastatic and antiangiogenic molecules are all in early clinical trials. I think it unlikely that we will be able to unify such diverse mechanisms under one clinical trial strategy, and this will |
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