needs, it is, all things considered, in the interest of the public’s health for the drug to enter the marketplace. In other words, the benefits of the drug outweigh its risks for the intended use and population. Although at the time of approval knowledge about efficacy from small, short-term clinical-trial populations is limited, far less is known about the drug’s risks. Some adverse effects may be too rare to be identified in the small numbers of people who participate in premarketing studies. For example, although the premarketing clinical trials for a second-generation rotavirus vaccine involved relatively large numbers of research participants, the small, increased risk of intussusceptions with rotavirus vaccines was only identified in post-licensure safety monitoring (approximately 1 of every 51,000 to 68,000 vaccinated infants) (Greenberg, 2011; Patel et al., 2011). Other adverse events may have a latent period longer than the duration of premarketing trials or may occur in people who are unlike those who participated in the premarketing trials in relevant respects. For example, they may be less healthy, take other medications, or have comorbidities. Such patients are often excluded from or enrolled in small numbers in premarketing trials (Fung, 2001).
For several reasons, questions about the effectiveness of a drug in actual clinical practice may also remain at the time of approval (Borer et al., 2007; Hiatt, 2006; IOM, 2007a; Ray and Stein, 2006). Long drug exposure during the postmarketing period could lead to a loss of effectiveness as tolerance or resistance to the drug develops. The population taking an approved drug is likely to be more heterogeneous than the people who participated in premarketing clinical trials. The drug may not be as effective in the postmarketing general population as it was in the premarketing test population. Many factors can account for those differences, including differences in environmental factors, genetics, age, race, ethnicity, or sex; interactions with other drugs; comorbidities; and problems with drug adherence. For example, a person who has liver disease might not fully metabolize and activate a drug, leading to decreased clinical effectiveness. A drug approved on the basis of a surrogate endpoint might not be as effective in improving a clinical endpoint, for example tumor shrinkage may not correlate strongly with survival. Once a drug is allowed to enter the market, physicians are free to use it, on-label or off-label, for any indication, including those of which there may be little or no scientific evidence of effectiveness from premarketing trials.
In the remainder of this chapter, the committee outlines a three-stage framework for making regulatory decisions and how FDA could apply the framework as part of the lifecycle approach to drug safety discussed in Chapter 1. (See Box 2-1 for definitions of key terms used in this chapter.) The committee then proposes a BRAMP document as a mechanism for implementing a lifecycle approach to drug regulation and for making FDA’s decisions transparent. Figure 2-1 shows how FDA can incorporate the framework and the BRAMP into a lifecycle approach to drug oversight. The chapter concludes by addressing the circumstance under which regulatory decisions should include requiring manufacturers to conduct postmarketing studies, a focus of the committee’s charge (see