needs to be carefully defined so neither the benefits nor risks differ appreciably from what would be expected in common use. Unless precluded by toxicity or tolerability, it would be expected that the dose of the comparator should be at least equal in effectiveness to the target agent. If no comparator treatment exists or no comparator has a well-defined benefit–risk profile, then typically at least one arm of the study should be some form of “usual care” or a placebo if usual care is not a proven or active treatment. If there are ethical reasons for not having a usual-care or placebo arm in the study—for example, if the treatment in question is for an irreversible and fatal disease—a treatment that does not have a well-defined benefit–risk profile might be the only ethically acceptable comparator. In such cases, FDA should take the questionable benefit–risk profiles of the drug and its comparator into account when interpreting the results of the study.


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