Modest evidence of an adverse effect on an efficacy endpoint may be sufficient to rule out a clinically meaningful benefit even if the point estimate does not exclude a null effect. On the other hand, if benefit on one endpoint is established (for example, cardiovascular health), but the trial is being done to assess a suspected harm on a different endpoint (for example, gastrointestinal bleeding), a higher standard of proof of the harm signal might be required. The Women’s Health Initiative trial, for example, stopped its estrogen–progestin arm because the breast-cancer outcome crossed the pre-specified safety boundary and because the global index outcome just trended in the direction of harm, effectively ruling out a substantive net benefit (Rossouw et al., 2002; Wittes et al., 2007).

Other issues that affect the evidence threshold for stopping for harm are whether and how external information is used. If an emerging signal of harm is similar to that seen in external studies, it is ethically justified and may be ethically required to halt a study earlier than if such evidence did not exist (Pocock, 1996).

International Challenges

The ability of FDA to discharge its ethical obligations to ensure adequate oversight of the postmarketing studies it requires is complicated when studies are conducted outside of the United States (Office of Inspector General, 2010). During the past two decades, the volume of premarketing clinical trials conducted outside the United States has increased dramatically, with many of these studies occurring in economically developing countries (Thiers et al., 2008; Wadman, 2007). Particularly when studies are conducted in resource poor countries, concerns have been raised about the quality, reliability and transportability of research results, and about the adequacy of research participant protections (HHS, 2001; Kimmelman et al., 2009; Lavery, 2004; NBAC, 2001). The committee recognizes that these concerns may apply as well to FDA required postmarketing research.

As the TIDE experience suggests, FDA required postmarketing trials are also being conducted at sites outside the United States. For example, the TIDE trial was conducted at 190 sites in more than 20 countries. Some of the countries in which the TIDE trial was conducted had research and oversight infrastructures equivalent or superior to those in the United States, but others did not have equivalent systems. Concerns about research quality and participant protections in some non-US sites pose challenges for FDA’s obligations to ensure adequate protection of the rights and interests of research participants in premarketing and postmarketing research that it requires and to ensure that such research can provide the evidence needed to identify the appropriate regulatory response to a public health question. The International Research Panel of the Presidential Commission for the Study of Bioethical Issues found that “ongoing international dialogue between U.S. and international bodies is critical to protecting human subjects in research” (PCSBI, 2011). FDA’s Office of International Programs,



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