whether they are willing to accept the risk solely to contribute to the public good.

•  Minimization of additional net risk by careful study design and implementation of a robust monitoring plan throughout the study.

•  Inclusion of special measures in the process of soliciting informed consent to confirm that patients understand and willingly accept that they are assuming an additional net risk—beyond what they are likely to face in clinical practice—solely in the interest of the public good.

•  Implementation of processes to ensure that over the course of the trial participants are regularly informed of any changes in clinical practice or the medical literature that are relevant to assessments of the comparative benefits and risks of trial participation and (non-research) clinical management.

External IRBs and data monitoring committees (DMCs) overseeing FDA-required postmarketing RCTs should have all the information necessary to ensure that the trials they oversee are ethically acceptable and adequately monitored. To that end, FDA should provide all relevant IRBs (centralized and multiple IRBs) and DMCs with sufficient information to permit appropriate continuing oversight of the RCT in accordance with their roles. That should include information about the public health question at issue, the specifics of the study design that it has deemed suitable to address the question—including any design features that it views as necessary for the ethical justification of the study, and any changes in clinical practice or professional standards that arise over the course of the RCT that might affect the benefit–risk profile of the drug and influence a person’s decision about whether to continue to participate.

Under what circumstances should head-to-head randomized clinical trials for safety be required?

The committee’s answer to this question assumes that it has already been determined, according to the criteria and processes outlined elsewhere in this report, that it is appropriate for FDA to require a postmarketing study and that this study should be an RCT.

A head-to-head trial involves a comparison of two active treatments that are both indicated for the same patients who have the same condition. The committee considered study designs in the context of a public health question about the benefits or risks associated with a drug. The public health question is most likely to be addressed by comparing the drug at issue with the therapies likely to be used if the drug were removed from the market or its use were restricted; that is the decision-relevant public health question. However, for such a study to be scientifically valid and ethical, the active comparator must have a well-defined benefit–risk profile and be a clinically acceptable alternative. The dose of the comparator



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